Substituted oxazines as beta-secretase inhibitors

ABSTRACT

The present disclosure provides a class of compounds useful for the modulation of beta-secretase enzyme (BACE) activity. The compounds have a general Formula I: (insert Formula I structure) wherein variables W, X, Y, R 2 , R 2′ , R 3 , R 4 , R 5 , R 6 , and R 7  of Formula I are defined herein. This disclosure also provides pharmaceutical compositions comprising the compounds, and uses of the compounds and compositions for treatment of disorders and/or conditions related to beta amyloid (Aβ) plaque formation and deposition, resulting from the biological activity of BACE. Such BACE mediated disorders include, for example, Alzheimer&#39;s Disease, cognitive deficits, cognitive impairments, and other central nervous system conditions.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a national stage application under 35 U.S.C. § 371of International Application No. PCT/US2017/066177, having aninternational filing date of Dec. 13, 2017, which claims the benefit ofU.S. Provisional Patent Application No. 62/434,711, filed Dec. 15, 2016and U.S. Provisional Patent Application No. 62/570,425, filed Oct. 10,2017, each of which is incorporated by reference herein in its entirety.

FIELD

The present disclosure relates generally to pharmaceutically activecompounds and pharmaceutical compositions thereof for the modulation ofbeta site amyloid precursor protein cleaving enzyme (BACE) activity.Provided herein are uses of these compounds and pharmaceuticalcompositions thereof for treatment of disorders and/or conditionsrelated to beta-amyloid plaque formation and deposition, resulting fromthe biological activity of BACE. Such BACE mediated disorders include,for example, Alzheimer's disease, cognitive deficits, cognitiveimpairments, and other central nervous system conditions.

BACKGROUND

Alzheimer's disease (AD) affects greater than 12 million aging peopleworldwide, and, importantly, the number affected continues to grow. ADaccounts for the majority of dementias clinically diagnosed after theage of 60. AD is generally characterized by the progressive decline ofmemory, reasoning, judgement and orientation. As the disease progresses,motor, sensory, and vocal abilities are affected until there is globalimpairment of multiple cognitive functions. The loss of cognitivefunction occurs gradually. Patients with severe cognitive impairmentand/or diagnosed as end-stage AD are generally bedridden, incontinent,and dependent on custodial care. The AD patient eventually dies in aboutnine to ten years, on average, after initial diagnosis. Due to theincapacitating, generally humiliating and ultimately fatal effects ofAD, there is a need to treat AD effectively upon diagnosis.

AD is characterized by two major physiological changes in the brain. Thefirst change, beta amyloid plaque formation, supports the “amyloidcascade hypothesis” which conveys the thought that AD is caused by theformation of characteristic beta amyloid (Aβ) peptide deposits in thebrain (commonly referred to as Aβ “plaques” or “plaque deposits”) and incerebral blood vessels (beta amyloid angiopathy). A wealth of evidencesuggests that Aβ and accompanying amyloid plaque formation is central tothe pathophysiology of AD and is likely to play an early role in thisintractable neurodegenerative disorder. Yan et al., Lancet Neurol.13(3):319-329 (2014). The second change in AD is the formation ofintraneuronal tangles, consisting of an aggregate form of themicrotubule-binding protein tau. Besides being found in patients withAD, intraneuronal tangles are also found in other dementia-inducingdisorders. Joachim et al., Alzheimer. Dis. Assoc. Disord. 6(1):7-34(1992).

Several lines of evidence indicate that progressive cerebral depositionof Aβ peptide plays a seminal role in the pathogenesis of AD and canprecede cognitive symptoms by years or even decades. Selkoe, Neuron6(4):487-498 (1991). Release of Aβ peptide from neuronal cells grown inculture and the presence of Aβ peptide in cerebrospinal fluid (CSF) ofboth normal individuals and AD patients has been demonstrated. Seubertet al., Nature 359:325-327 (1992). Autopsies of AD patients haverevealed large numbers of lesions comprising Aβ and tau peptides inareas of the human brain believed to be important for memory andcognition.

Smaller numbers of these lesions in a more restricted anatomicaldistribution are found in the brains of most aged humans who do not haveclinical AD. Amyloid containing plaques and vascular amyloid angiopathywere also found in the brains of individuals with Down's syndrome,Hereditary Cerebral Hemorrhage with Amyloidosis of the Dutch-type(HCHWA-D), and other neurodegenerative disorders.

It has been hypothesized that Aβ peptide formation is a causativeprecursor or factor in the development of AD. More specifically,deposition of Aβ peptide in areas of the brain responsible for cognitionis believed to be a major factor in the development of AD. Aβ plaquesare primarily composed of Aβ peptide. Aβ peptide is derived from theproteolytic cleavage of a large transmembrane amyloid precursor protein(APP), and is a peptide comprised of about 39-42 amino acid residues. Aβ1-42 (42 amino acids long) is thought to be the major component of theseplaque deposits in the brains of AD patients. Citron, Trends Pharmacol.Sci. 25(2):92-97 (2004).

Similar plaques appear in some variants of Lewy body dementia and ininclusion body myositis, a muscle disease. Aβ peptides also formaggregates coating cerebral blood vessels in cerebral amyloidangiopathy. These plaques are composed of fibrillar Aβ aggregates thatdisplay a characteristic β-sheet structure, a protein fold shared byother peptides such as prions associated with protein misfoldingdiseases. Research on laboratory rats suggest that the dimeric, solubleform of the peptide is a causative agent in the development of AD and isthe smallest synaptotoxic species of soluble amyloid beta oligomer.Shankar et al., Nat. Med. 14(8):837-842 (2008).

Several aspartyl proteases, including β-secretase and γ-secretase, areinvolved in the processing or cleavage of APP, resulting in theformation of Aβ peptide. β-Secretase (BACE, also commonly referred to asmemapsin) is the first to cleave APP to generate two fragments: (1) afirst N-terminus fragment (sAPPβ) and (2) a second C-99 fragment, whichis subsequently cleaved by γ-secretase to generate the Aβ peptide. APPhas also been found to be cleaved by α-secretase to produce sAPPα, asecreted form of APP that does not result in Aβ plaque formation. Thisalternate pathway precludes the formation of Aβ peptide. A descriptionof the proteolytic processing fragments of APP is found, for example, inU.S. Pat. Nos. 5,441,870, 5,712,130 and 5,942,400.

BACE is an aspartyl protease enzyme comprising 501 amino acids andresponsible for processing APP at the β-secretase specific cleavagesite. BACE is present in two forms, BACE 1 and BACE 2, designated assuch depending upon the specific cleavage site of APP. β-Secretase isdescribed in Sinha et al., Nature 402:537-540 (1999) and InternationalPatent Application Publication No. WO2000/017369. It has been proposedthat Aβ peptide accumulates as a result of APP processing initiated byBACE. Moreover, in vivo processing of APP at the β-secretase cleavagesite is thought to be a rate-limiting step in Aβ peptide production.Sabbagh et al., Alzheimer's Disease Review 3:1-19 (1997). Thus,inhibition of the BACE enzyme activity is desirable for the treatment ofAD.

Studies have shown that the inhibition of BACE may be linked to thetreatment of AD. The BACE enzyme is essential for the generation of Aβpeptide. BACE knockout mice do not produce Aβ peptide and are free fromAD associated pathologies including neuronal loss and certain memorydeficits. Cole et al., Molecular Neurodegeneration 2:22, pages 1-25(2007). When crossed with transgenic mice that over express APP, theprogeny of BACE deficient mice show reduced amounts of Aβ peptide inbrain extracts as compared with control animals. Luo et al., Nat.Neurosci. 4(3):231-232 (2001). The fact that BACE initiates theformation of Aβ peptide, and the observation that BACE levels areelevated in this disease provide direct and compelling reasons todevelop therapies directed at BACE inhibition, thus, reducing Aβ peptideformation and its associated toxicities. To this end, inhibition ofβ-secretase activity and a corresponding reduction of Aβ peptide in thebrain should provide a therapeutic method for treating AD and other Aβpeptide or plaque related disorders.

Consequently, the approach of regulating or reducing Aβ peptideformation and deposition as a potential treatment for AD has receivedtremendous attention, support and commitment from both researchers andinvestors alike. A small molecule γ-secretase inhibitor, LY450139(“Semagacestat”), an Aβ peptide lowering agent, advanced to phase IIIclinical trials for the treatment of AD. The pharmacokinetics ofsemagacestat in plasma, as well as the plasma and cerebral spinal fluid(CSF) Aβ peptide levels as pharmacodynamic responses to semagacestatadministration were evaluated in healthy human subjects in single andmultiple doses, and pharmacokinetic and pharmacodynamic changes werealso assessed in mild to moderate AD patients in two (2) clinical trials(Henley et al., Expert Opin. Pharmacother. 10(10):1657-1664 (2009);Siemers et al., Clin. Neuropharmacol. 30(6): 317-325 (2007); and Siemerset al., Neurology 66(4):602-604 (2006)). Additional approaches have beentaken in attempts to treat AD and plaque-related disorders. See, forexample, Yan et al., Lancet Neurology 13(3):319-329 (2014).

Furthermore, each of the following exemplary patent applicationpublications describes inhibitors of BACE, useful for treating AD andother β-secretase mediated disorders: WO2014/098831, WO2014/099794,WO2014/099788, WO2014/097038, WO2014/093190, WO2014/066132,WO2014/065434, WO2014/062553, WO2014/062549, WO2014/045162,WO2014/013076, WO2013/182638, WO2013/164730, WO2013/030713,WO2013/028670, WO2013/004676, WO2012/162334, WO2012/162330,WO2012/147762, WO2012/139425, WO2012/138734, US2012/0245157,US2012/0245154, US2012/0238557, WO2011/029803, WO2011/005738,US2011/0152253, WO2010/013794, WO2010/013302, US2010/0160290,US2010/0075957, WO2009/151098, WO2009/134617, US2009/0209755,US2009/0082560, EP2703401 (equivalent of WO2012/146762) and EP1942105.

The lysosomal aspartic protease Cathepsin D (CatD) is ubiquitouslyexpressed in eukaryotic organisms. CatD activity is essential toaccomplish the acid-dependent extensive or partial proteolysis ofprotein substrates within endosomal and lysosomal compartments thereindelivered via endocytosis, phagocytosis or autophagocytosis. CatD mayalso act at physiological pH on small-size substrates in the cytosol andin the extracellular milieu. Mouse and fruit fly CatD knock-out modelshave highlighted the multi-pathophysiological roles of CatD in tissuehomeostasis and organ development.

Inhibition of protein CatD has been implicated in undesirable sideeffects. For instance, the inhibition of CatD is believed to be linkedto adverse retinal development and retinal atrophy. Particularly, inmice it was found that CatD is essential for the metabolic maintenanceof retinal photoreceptor cells and that its deficiency induces apoptosisof the cells, while the loss of inner nuclear layer (INL) neurons ismediated by nitric oxide release from microglial cells. However, in thevery same mice, it was also found that no atrophic change was detectedin the retina of mice deficient in Cathepsin B or L. Koike et al., Mol.Cell Neurosci. 22(2):146-161 (2003). Further, animal models of CatDdeficiency are characterized by a progressive and relentlessneurodegenerative phenotype similar to that observed in Neuronal CeroidLipofuscinoses (NCL), a group of pediatric neurodegenerative diseasesknown collectively as Batten Disease. It has been shown that thetargeted deletion of the pro-apoptotic molecule Bax prevents apoptoticmarkers, but not neuronal cell death and neurodegeneration induced byCatD deficiency, which suggests that alterations in themacroautophagy-lysosomal degradation pathway can mediate neuronal celldeath in NCL/Batten Disease in the absence of apoptosis. Shacka et al.,Autophagy 3(5):474-476 (2007). Finally, an adverse effect of theinhibition of CatD is evident from the data presented in Folio et al.,PLoS One 6(7):e21908 (2011). The authors of the PLoS One paper foundthat knock-down of CatD affects the retinal pigment epithelium, impairsswim-bladder ontogenesis and causes premature death in zebrafish. Themain phenotypic alterations produced by CatD knock-down in zebrafishwere: 1. abnormal development of the eye and of retinal pigmentepithelium; 2. absence of the swim-bladder; 3. skin hyper-pigmentation;4. reduced growth and premature death. Rescue experiments confirmed theinvolvement of CatD in the developmental processes leading to thesephenotypic alterations.

Moreover, such toxicity findings which, in view of the literature, mayhave played a role in the termination of a human BACE-mediated ADclinical trial. Eli Lilly terminated a phase I clinical trial of LY2811376 after rat toxicology studies showed that a higher compound dosegiven for three months damaged the pigment epithelium of the rat's eye.The retinal layer had inclusions and extensive damage. The Phase Idosing trial was terminated and people brought in for eye assessmentsdid not show any abnormalities. (Alzheimer's Research Forum News, Mar.31, 2011 reporting on Martin Citron's presentation at the AD/PDConference 3-2011 in Barcelona, Spain).

Hence, it is desirable to provide compounds which modulate the activityof and are selective for BACE, while not suffering from undesirable sideeffects possibly due to intervention with or the reduction and/or director indirect inhibition of the expression and/or function of otherproteins or biological pathways.

SUMMARY

The compounds disclosed herein are useful for the modulation ofβ-secretase activity, and as treatment of AD. Particularly, thecompounds provided herein are useful for the regulation or reduction ofthe formation of Aβ peptide and, consequently, the regulation and/orreduction of formation of Aβ plaque both in the brain, as well as in theCNS. To this end, the compounds are useful for the treatment of AD andother β-secretase and/or plaque-related and/or mediated disorders. Forexample, the compounds are useful for the prophylaxis and/or treatment,acute and/or chronic, of AD and other diseases or conditions involvingthe deposition or accumulation of Aβ peptide, and formation of plaque,in the brain.

First, provided herein is a compound of Formula I

or a tautomer thereof, or a pharmaceutically acceptable salt of saidcompound or tautomer, wherein

W is N or CH;

X is O or C(R¹R^(1′));

Y is O or C(R¹R^(1′)); wherein

-   -   (1) X is O and Y is C(R¹R^(1′)) or    -   (2) X is C(R¹R^(1′)) and Y is O;

R¹ and R^(1′), independently, are H or C₁₋₆alkyl, wherein the C₁₋₆alkylis optionally substituted with one to three fluoro substituents;

R² and R^(2′), independently, are H, halogen, or C₁₋₆alkoxy, wherein theC₁₋₆alkoxy is optionally substituted with one to three fluorosubstituents;

alternatively, if X is O and Y is C(R¹R^(1′)) and R^(1′) and R^(2′) areboth H, then R¹ and R² together with the carbon atoms to which they areattached may form a C₃₋₆cycloalkyl ring;

R³ is C₁₋₄alkyl optionally substituted with one to three fluorosubstituents;

R⁴ is halogen;

R⁵ is H or F; and

one of R⁶ and R⁷ is F or H and the other of R⁶ and R⁷ is a 6-memberednitrogen-containing heteroaryl, which heteroaryl is optionallysubstituted with one or two substituents selected from halogen, —CN,C₁₋₆alkyl, C₁₋₆alkoxy, 2-propynyloxy, or 2-butynyloxy, wherein theC₁₋₆alkyl or C₁₋₆alkoxy are optionally substituted with one to fivefluoro substituents.

Second, provided herein are pharmaceutical compositions comprising acompound of Formula I and a pharmaceutically acceptable excipient.

Third, provided herein are compounds of Formula I or pharmaceuticalcompositions thereof for use as a medicament.

Fourth, provided herein are compounds of Formula I or pharmaceuticalcompositions thereof for use in reducing beta amyloid peptide levels inthe cerebral spinal fluid of a subject.

Fifth, provided herein are compounds of Formula I or pharmaceuticalcompositions thereof for use in treating Alzheimer's disease, cognitiveimpairment, or a combination thereof in a subject. In addition, providedherein are compounds of Formula I or pharmaceutical compositions thereoffor use in treating a neurological disorder selected from mild cognitiveimpairment, Down's syndrome, hereditary cerebral hemorrhage withDutch-type amyloidosis, cerebral amyloid angiopathy, degenerativedementia, dementia associated with Parkinson's disease, dementiaassociated with supranuclear palsy, dementia associated with corticalbasal degeneration, diffuse Lewy body type of Alzheimer's disease, or acombination thereof in a subject.

Sixth, provided herein are compounds of Formula I or pharmaceuticalcompositions thereof for use in reducing formation of plaque in thebrain of a subject.

Reference will now be made in detail to embodiments of the presentdisclosure. While certain embodiments of the present disclosure will bedescribed, it will be understood that it is not intended to limit theembodiments of the present disclosure to those described embodiments. Tothe contrary, reference to embodiments of the present disclosure isintended to cover alternatives, modifications, and equivalents as may beincluded within the spirit and scope of the embodiments of the presentdisclosure as defined by the appended claims.

DETAILED DESCRIPTION

Provided herein as Embodiment 1 is a compound of Formula I

or a tautomer thereof, or a pharmaceutically acceptable salt of saidcompound or tautomer, wherein

W is N or CH;

X is O or C(R¹R^(1′));

Y is O or C(R¹R^(1′)); wherein

-   -   (1) X is O and Y is C(R¹R^(1′)) or    -   (2) X is C(R¹R^(1′)) and Y is O;

R¹ and R^(1′), independently, are H or C₁₋₆alkyl, wherein the C₁₋₆alkylis optionally substituted with one to three fluoro substituents;

R² and R^(2′), independently, are H, halogen, or C₁₋₆alkoxy, wherein theC₁₋₆alkoxy is optionally substituted with one to three fluorosubstituents;

alternatively, if X is O and Y is C(R¹R^(1′)) and R^(1′) and R^(2′) areboth H, then R¹ and R² together with the carbon atoms to which they areattached may form a C₃₋₆cycloalkyl ring;

R³ is C₁₋₄alkyl optionally substituted with one to three fluorosubstituents;

R⁴ is halogen;

R⁵ is H or F; and

one of R⁶ and R⁷ is F or H and the other of R⁶ and R⁷ is a 6-memberednitrogen-containing heteroaryl, which heteroaryl is optionallysubstituted with one or two substituents selected from halogen, —CN,C₁₋₆alkyl, C₁₋₆alkoxy, 2-propynyloxy, or 2-butynyloxy, wherein theC₁₋₆alkyl or C₁₋₆alkoxy are optionally substituted with one to fivefluoro substituents.

Provided herein as Embodiment 2 is the compound according to Embodiment1, or a tautomer thereof, or a pharmaceutically acceptable salt of saidcompound or tautomer, wherein the compound of Formula I is a compound ofFormula II

Provided herein as Embodiment 3 is the compound according to Embodiment1, or a tautomer thereof, or a pharmaceutically acceptable salt of saidcompound or tautomer, wherein the compound of Formula I is a compound ofFormula IIIA

Provided herein as Embodiment 4 is the compound according to Embodiment1, or a tautomer thereof, or a pharmaceutically acceptable salt of saidcompound or tautomer, wherein the compound of Formula I is a compound ofFormula IIIA′

Provided herein as Embodiment 5 is the compound according to Embodiment1, or a tautomer thereof, or a pharmaceutically acceptable salt of saidcompound or tautomer, wherein the compound of Formula I is a compound ofFormula IIIB

Provided herein as Embodiment 6 is the compound according to Embodiment1, or a tautomer thereof, or a pharmaceutically acceptable salt of saidcompound or tautomer, wherein the compound of Formula I is a compound ofFormula IIIB′

Provided herein as Embodiment 7 is the compound according to Embodiment1, or a tautomer thereof, or a pharmaceutically acceptable salt of saidcompound or tautomer, wherein the compound of Formula I is a compound ofFormula IIIC

Provided herein as Embodiment 8 is the compound according to Embodiment1, or a tautomer thereof, or a pharmaceutically acceptable salt of saidcompound or tautomer, wherein the compound of Formula I is a compound ofFormula IIIC′

Provided herein as Embodiment 9 is the compound according to any one ofEmbodiments 1 and 2, or a tautomer thereof, or a pharmaceuticallyacceptable salt of said compound or tautomer, wherein X is O and Y isC(R¹R^(1′)).

Provided herein as Embodiment 10 is the compound according to any one ofEmbodiments 1 and 2, or a tautomer thereof, or a pharmaceuticallyacceptable salt of said compound or tautomer, wherein X is C(R¹R^(1′))and Y is O.

Provided herein as Embodiment 11 is the compound according to any one ofEmbodiments 1 and 2, or a tautomer thereof, or a pharmaceuticallyacceptable salt of said compound or tautomer, wherein

X is O and Y is C(R¹R^(1′));

R^(1′) and R^(2′) are both H; and

R¹ and R² together with the carbon atoms to which they are attached forma cyclopropyl ring.

Provided herein as Embodiment 12 is the compound according to any one ofEmbodiments 1-3 and 7-10, or a tautomer thereof, or a pharmaceuticallyacceptable salt of said compound or tautomer, wherein R¹ or R^(1′),independently, are H, methyl, or trifluoromethyl.

Provided herein as Embodiment 13 is the compound according to any one ofEmbodiments 1-3 and 7-10, or a tautomer thereof, or a pharmaceuticallyacceptable salt of said compound or tautomer, wherein R¹ and R^(1′) areH.

Provided herein as Embodiment 14 is the compound according to any one ofEmbodiments 1-3 and 7-10, or a tautomer thereof, or a pharmaceuticallyacceptable salt of said compound or tautomer, wherein R¹ is methyl andR^(1′) is trifluoromethyl.

Provided herein as Embodiment 15 is the compound according to any one ofEmbodiments 1-4, or a tautomer thereof, or a pharmaceutically acceptablesalt of said compound or tautomer, wherein R² and R^(2′), independently,are H, F, or —OCH₂CF₃.

Provided herein as Embodiment 16 is the compound according to any one ofEmbodiments 1-4, or a tautomer thereof, or a pharmaceutically acceptablesalt of said compound or tautomer, wherein R² and R^(2′) are F.

Provided herein as Embodiment 17 is the compound according to any one ofEmbodiments 1-4, or a tautomer thereof, or a pharmaceutically acceptablesalt of said compound or tautomer, wherein R² is H and R^(2′) is—OCH₂CF₃.

Provided herein as Embodiment 18 is the compound according to any one ofEmbodiments 1-17, or a tautomer thereof, or a pharmaceuticallyacceptable salt of said compound or tautomer, wherein R³ is methyl,monofluoromethyl, difluoromethyl, or trifluoromethyl.

Provided herein as Embodiment 19 is the compound according to any one ofEmbodiments 1-17, or a tautomer thereof, or a pharmaceuticallyacceptable salt of said compound or tautomer, wherein R³ is methyl ordifluoromethyl.

Provided herein as Embodiment 20 is the compound according to any one ofEmbodiments 1-19, or a tautomer thereof, or a pharmaceuticallyacceptable salt of said compound or tautomer, wherein R⁴ is F.

Provided herein as Embodiment 21 is the compound according to any one ofEmbodiments 1-20, or a tautomer thereof, or a pharmaceuticallyacceptable salt of said compound or tautomer, wherein R⁶ and R⁷ is F orH and the other of R⁶ and R⁷ is pyridyl or pyrazinyl, which pyridyl orpyrazinyl is optionally substituted with one or two substituentsselected from Cl, Br, —CN, —CF₃, —OCF₂CHF₂, 2-propynyloxy, or2-butynyloxy.

Provided herein as Embodiment 22 is the compound according to any one ofEmbodiments 1-20, or a tautomer thereof, or a pharmaceuticallyacceptable salt of said compound or tautomer, wherein R⁶ and R⁷ is F orH and the other of R⁶ and R⁷ is pyridyl or pyrazinyl, which pyridyl orpyrazinyl is optionally substituted with Cl, Br, —CN, —OCF₂CHF₂,2-propynyloxy, or 2-butynyloxy.

Provided herein as Embodiment 23 is the compound according to any one ofEmbodiments 1-20, or a tautomer thereof, or a pharmaceuticallyacceptable salt of said compound or tautomer, wherein R⁶ and R⁷ is F orH and the other of R⁶ and R⁷ is pyridyl or pyrazinyl, which pyridyl orpyrazinyl is optionally substituted with Br, —CN, —OCF₂CHF₂,2-propynyloxy, or 2-butynyloxy.

Provided herein as Embodiment 24 is the compound according to any one ofEmbodiments 1-22, or a tautomer thereof, or a pharmaceuticallyacceptable salt of said compound or tautomer, wherein one of R⁶ and R⁷is

Provided herein as Embodiment 25 is the compound according to any one ofEmbodiments 1-25, or a tautomer thereof, or a pharmaceuticallyacceptable salt of said compound or tautomer, wherein one of R⁶ and R⁷is

Provided herein as Embodiment 26 is the compound according to any one ofEmbodiments 1-25, or a tautomer thereof, or a pharmaceuticallyacceptable salt of said compound or tautomer, wherein

W is CH.

Provided herein as Embodiment 27 is the compound according to any one ofEmbodiments 1-25, or a tautomer thereof, or a pharmaceuticallyacceptable salt of said compound or tautomer, wherein

W is N.

Provided herein as Embodiment 28 is the compound according to any one ofEmbodiments 1-27, or a tautomer thereof, or a pharmaceuticallyacceptable salt of said compound or tautomer, wherein

R⁵ is H; and

R⁶ is H.

Provided herein as Embodiment 29 is the compound according to any one ofEmbodiments 1-27, or a tautomer thereof, or a pharmaceuticallyacceptable salt of said compound or tautomer, wherein

R⁵ is H; and

R⁷ is H.

Provided herein as Embodiment 30 is the compound according to any one ofEmbodiments 1-27, or a tautomer thereof, or a pharmaceuticallyacceptable salt of said compound or tautomer, wherein

R⁵ is F; and

R⁶ is H.

Provided herein as Embodiment 31 is the compound according to any one ofEmbodiments 1-27, or a tautomer thereof, or a pharmaceuticallyacceptable salt of said compound or tautomer, wherein

R⁵ is F; and

R⁷ is H.

Provided herein as Embodiment 32 is the compound according to any one ofEmbodiments 1-27, or a tautomer thereof, or a pharmaceuticallyacceptable salt of said compound or tautomer, wherein

R⁵ is H; and

R⁶ is F.

Provided herein as Embodiment 33 is the compound according to any one ofEmbodiments 1-27, or a tautomer thereof, or a pharmaceuticallyacceptable salt of said compound or tautomer, wherein

R⁵ is H; and

R⁷ is F.

Provided herein as Embodiment 34 is the compound of Embodiment 1, or atautomer thereof, or a pharmaceutically acceptable salt of said compoundor tautomer, selected from

-   (1R,5S,6R)-5-(5-((Z)-2-(5-bromopyridin-2-yl)-2-fluorovinyl)-2-fluorophenyl)-5-(difluoromethyl)-2-oxa-4-azabicyclo[4.1.0]hept-3-en-3-amine;-   (1R,5S,6R)-5-(5-((Z)-2-(5-chloropyridin-2-yl)-2-fluorovinyl)-2-fluorophenyl)-5-(difluoromethyl)-2-oxa-4-azabicyclo[4.1.0]hept-3-en-3-amine;-   6-((Z)-2-(3-((1R,5S,6R)-3-amino-5-(difluoromethyl)-2-oxa-4-azabicyclo[4.1.0]hept-3-en-5-yl)-4-fluorophenyl)-1-fluorovinyl)nicotinonitrile;-   (2R,5R)-5-(5-((Z)-2-(5-chloropyridin-2-yl)-2-fluorovinyl)-2-fluorophenyl)-2,5-dimethyl-2-(trifluoromethyl)-5,6-dihydro-2H-1,4-oxazin-3-amine;-   6-((Z)-2-(3-((3R,6R)-5-amino-3,6-dimethyl-6-(trifluoromethyl)-3,6-dihydro-2H-1,4-oxazin-3-yl)-4-fluorophenyl)-1-fluorovinyl)nicotinonitrile;-   5-((Z)-2-(3-((3R,6R)-5-amino-3,6-dimethyl-6-(trifluoromethyl)-3,6-dihydro-2H-1,4-oxazin-3-yl)-4-fluorophenyl)-1-fluorovinyl)pyrazine-2-carbonitrile;-   (2R,5R)-5-(2-fluoro-5-((Z)-2-fluoro-2-(5-(2,2,3,3-tetrafluoropropoxy)pyrazin-2-yl)vinyl)phenyl)-2,5-dimethyl-2-(trifluoromethyl)-5,6-dihydro-2H-1,4-oxazin-3-amine;-   (2R,5R)-5-(2-fluoro-5-((Z)-2-fluoro-2-(5-(prop-2-yn-1-yloxy)pyrazin-2-yl)vinyl)phenyl)-2,5-dimethyl-2-(trifluoromethyl)-5,6-dihydro-2H-1,4-oxazin-3-amine;-   (2R,5R)-5-(5-((Z)-2-(5-chloropyrazin-2-yl)-2-fluorovinyl)-2-fluorophenyl)-2,5-dimethyl-2-(trifluoromethyl)-5,6-dihydro-2H-1,4-oxazin-3-amine;-   6-((Z)-2-(3-((4R,5R)-2-amino-4-methyl-5-(2,2,2-trifluoroethoxy)-5,6-dihydro-4H-1,3-oxazin-4-yl)-4-fluorophenyl)-1-fluorovinyl)nicotinonitrile;-   (4R,5R)-4-(5-((Z)-2-(5-chloropyrazin-2-yl)-2-fluorovinyl)-2-fluorophenyl)-4-methyl-5-(2,2,2-trifluoroethoxy)-5,6-dihydro-4H-1,3-oxazin-2-amine;-   (4R,5R)-4-(2-fluoro-5-((Z)-2-fluoro-2-(5-(prop-2-yn-1-yloxy)pyrazin-2-yl)vinyl)phenyl)-4-methyl-5-(2,2,2-trifluoroethoxy)-5,6-dihydro-4H-1,3-oxazin-2-amine;-   5-((Z)-2-(3-((4R,5R)-2-amino-4-methyl-5-(2,2,2-trifluoroethoxy)-5,6-dihydro-4H-1,3-oxazin-4-yl)-4-fluorophenyl)-1-fluorovinyl)pyrazine-2-carbonitrile;-   (4R,5R)-4-(5-((Z)-2-(5-(but-2-yn-1-yloxy)pyrazin-2-yl)-2-fluorovinyl)-2-fluorophenyl)-4-methyl-5-(2,2,2-trifluoroethoxy)-5,6-dihydro-4H-1,3-oxazin-2-amine;-   (R,Z)-6-(2-(3-(2-amino-5,5-difluoro-4-methyl-5,6-dihydro-4H-1,3-oxazin-4-yl)-4-fluorophenyl)-1-fluorovinyl)nicotinonitrile;-   (R,Z)-5,5-difluoro-4-(2-fluoro-5-(2-fluoro-2-(5-(prop-2-yn-1-yloxy)pyrazin-2-yl)vinyl)phenyl)-4-methyl-5,6-dihydro-4H-1,3-oxazin-2-amine;    or-   (R,Z)-6-(2-(6-(2-amino-5,5-difluoro-4-methyl-5,6-dihydro-4H-1,3-oxazin-4-yl)-5-fluoropyridin-2-yl)-1-fluorovinyl)nicotinonitrile.

Provided herein as a first alternative Embodiment 34 is an Embodiment,wherein the compound is(2R,5R)-5-(6-((Z)-2-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)-2-fluorovinyl)-3-fluoropyridin-2-yl)-2,5-dimethyl-2-(trifluoromethyl)-5,6-dihydro-2H-1,4-oxazin-3-amine.

Provided herein as a second alternative Embodiment 34 is an Embodiment,wherein the compound is6-((Z)-2-(6-((3R,6R)-5-amino-3,6-dimethyl-6-(trifluoromethyl)-3,6-dihydro-2H-1,4-oxazin-3-yl)-5-fluoropyridin-2-yl)-1-fluorovinyl)-5-chloronicotinonitrile.

Provided herein as a third alternative Embodiment 34 is an Embodiment,wherein the compound is(2R,5R)-5-(6-((Z)-2-(3-amino-5-(trifluoromethyl)pyrazin-2-yl)-2-fluorovinyl)-3-fluoropyridin-2-yl)-2,5-dimethyl-2-(trifluoromethyl)-5,6-dihydro-2H-1,4-oxazin-3-amine.

Provided herein as a fourth alternative Embodiment 34 is the compound ofEmbodiment 1, or a tautomer thereof, or a pharmaceutically acceptablesalt of said compound or tautomer, selected from

-   (1R,5S,6R)-5-(5-((Z)-2-(5-bromopyridin-2-yl)-2-fluorovinyl)-2-fluorophenyl)-5-(difluoromethyl)-2-oxa-4-azabicyclo[4.1.0]hept-3-en-3-amine;-   (1R,5S,6R)-5-(5-((Z)-2-(5-chloropyridin-2-yl)-2-fluorovinyl)-2-fluorophenyl)-5-(difluoromethyl)-2-oxa-4-azabicyclo[4.1.0]hept-3-en-3-amine;-   6-((Z)-2-(3-((1R,5S,6R)-3-amino-5-(difluoromethyl)-2-oxa-4-azabicyclo[4.1.0]hept-3-en-5-yl)-4-fluorophenyl)-1-fluorovinyl)nicotinonitrile;-   (2R,5R)-5-(5-((Z)-2-(5-chloropyridin-2-yl)-2-fluorovinyl)-2-fluorophenyl)-2,5-dimethyl-2-(trifluoromethyl)-5,6-dihydro-2H-1,4-oxazin-3-amine;-   6-((Z)-2-(3-((3R,6R)-5-amino-3,6-dimethyl-6-(trifluoromethyl)-3,6-dihydro-2H-1,4-oxazin-3-yl)-4-fluorophenyl)-1-fluorovinyl)nicotinonitrile;-   5-((Z)-2-(3-((3R,6R)-5-amino-3,6-dimethyl-6-(trifluoromethyl)-3,6-dihydro-2H-1,4-oxazin-3-yl)-4-fluorophenyl)-1-fluorovinyl)pyrazine-2-carbonitrile;-   (2R,5R)-5-(2-fluoro-5-((Z)-2-fluoro-2-(5-(2,2,3,3-tetrafluoropropoxy)pyrazin-2-yl)vinyl)phenyl)-2,5-dimethyl-2-(trifluoromethyl)-5,6-dihydro-2H-1,4-oxazin-3-amine;-   (2R,5R)-5-(2-fluoro-5-((Z)-2-fluoro-2-(5-(prop-2-yn-1-yloxy)pyrazin-2-yl)vinyl)phenyl)-2,5-dimethyl-2-(trifluoromethyl)-5,6-dihydro-2H-1,4-oxazin-3-amine;-   (2R,5R)-5-(5-((Z)-2-(5-chloropyrazin-2-yl)-2-fluorovinyl)-2-fluorophenyl)-2,5-dimethyl-2-(trifluoromethyl)-5,6-dihydro-2H-1,4-oxazin-3-amine;-   6-((Z)-2-(3-((4R,5R)-2-amino-4-methyl-5-(2,2,2-trifluoroethoxy)-5,6-dihydro-4H-1,3-oxazin-4-yl)-4-fluorophenyl)-1-fluorovinyl)nicotinonitrile;-   (4R,5R)-4-(5-((Z)-2-(5-chloropyrazin-2-yl)-2-fluorovinyl)-2-fluorophenyl)-4-methyl-5-(2,2,2-trifluoroethoxy)-5,6-dihydro-4H-1,3-oxazin-2-amine;-   (4R,5R)-4-(2-fluoro-5-((Z)-2-fluoro-2-(5-(prop-2-yn-1-yloxy)pyrazin-2-yl)vinyl)phenyl)-4-methyl-5-(2,2,2-trifluoroethoxy)-5,6-dihydro-4H-1,3-oxazin-2-amine;-   5-((Z)-2-(3-((4R,5R)-2-amino-4-methyl-5-(2,2,2-trifluoroethoxy)-5,6-dihydro-4H-1,3-oxazin-4-yl)-4-fluorophenyl)-1-fluorovinyl)pyrazine-2-carbonitrile;-   (4R,5R)-4-(5-((Z)-2-(5-(but-2-yn-1-yloxy)pyrazin-2-yl)-2-fluorovinyl)-2-fluorophenyl)-4-methyl-5-(2,2,2-trifluoroethoxy)-5,6-dihydro-4H-1,3-oxazin-2-amine;-   (R,Z)-6-(2-(3-(2-amino-5,5-difluoro-4-methyl-5,6-dihydro-4H-1,3-oxazin-4-yl)-4-fluorophenyl)-1-fluorovinyl)nicotinonitrile;-   (R,Z)-5,5-difluoro-4-(2-fluoro-5-(2-fluoro-2-(5-(prop-2-yn-1-yloxy)pyrazin-2-yl)vinyl)phenyl)-4-methyl-5,6-dihydro-4H-1,3-oxazin-2-amine;-   (R,Z)-6-(2-(6-(2-amino-5,5-difluoro-4-methyl-5,6-dihydro-4H-1,3-oxazin-4-yl)-5-fluoropyridin-2-yl)-1-fluorovinyl)nicotinonitrile;    or-   6-((Z)-2-(6-((3R,6R)-5-amino-3,6-dimethyl-6-(trifluoromethyl)-3,6-dihydro-2H-1,4-oxazin-3-yl)-5-fluoropyridin-2-yl)-1-fluorovinyl)nicotinonitrile.

Provided herein as Embodiment 35 is the compound of Embodiment 1, or atautomer thereof, or a pharmaceutically acceptable salt of said compoundor tautomer, selected from

-   (1R,5S,6R)-5-(5-((Z)-2-(5-bromopyridin-2-yl)-2-fluorovinyl)-2-fluorophenyl)-5-(difluoromethyl)-2-oxa-4-azabicyclo[4.1.0]hept-3-en-3-amine;-   6-((Z)-2-(3-((1R,5S,6R)-3-amino-5-(difluoromethyl)-2-oxa-4-azabicyclo[4.1.0]hept-3-en-5-yl)-4-fluorophenyl)-1-fluorovinyl)nicotinonitrile;-   6-((Z)-2-(3-((3R,6R)-5-amino-3,6-dimethyl-6-(trifluoromethyl)-3,6-dihydro-2H-1,4-oxazin-3-yl)-4-fluorophenyl)-1-fluorovinyl)nicotinonitrile;-   5-((Z)-2-(3-((3R,6R)-5-amino-3,6-dimethyl-6-(trifluoromethyl)-3,6-dihydro-2H-1,4-oxazin-3-yl)-4-fluorophenyl)-1-fluorovinyl)pyrazine-2-carbonitrile;-   (2R,5R)-5-(2-fluoro-5-((Z)-2-fluoro-2-(5-(2,2,3,3-tetrafluoropropoxy)pyrazin-2-yl)vinyl)phenyl)-2,5-dimethyl-2-(trifluoromethyl)-5,6-dihydro-2H-1,4-oxazin-3-amine;-   (2R,5R)-5-(2-fluoro-5-((Z)-2-fluoro-2-(5-(prop-2-yn-1-yloxy)pyrazin-2-yl)vinyl)phenyl)-2,5-dimethyl-2-(trifluoromethyl)-5,6-dihydro-2H-1,4-oxazin-3-amine;-   6-((Z)-2-(3-((4R,5R)-2-amino-4-methyl-5-(2,2,2-trifluoroethoxy)-5,6-dihydro-4H-1,3-oxazin-4-yl)-4-fluorophenyl)-1-fluorovinyl)nicotinonitrile;-   (4R,5R)-4-(5-((Z)-2-(5-chloropyrazin-2-yl)-2-fluorovinyl)-2-fluorophenyl)-4-methyl-5-(2,2,2-trifluoroethoxy)-5,6-dihydro-4H-1,3-oxazin-2-amine;-   (4R,5R)-4-(2-fluoro-5-((Z)-2-fluoro-2-(5-(prop-2-yn-1-yloxy)pyrazin-2-yl)vinyl)phenyl)-4-methyl-5-(2,2,2-trifluoroethoxy)-5,6-dihydro-4H-1,3-oxazin-2-amine;-   5-((Z)-2-(3-((4R,5R)-2-amino-4-methyl-5-(2,2,2-trifluoroethoxy)-5,6-dihydro-4H-1,3-oxazin-4-yl)-4-fluorophenyl)-1-fluorovinyl)pyrazine-2-carbonitrile;-   (4R,5R)-4-(5-((Z)-2-(5-(but-2-yn-1-yloxy)pyrazin-2-yl)-2-fluorovinyl)-2-fluorophenyl)-4-methyl-5-(2,2,2-trifluoroethoxy)-5,6-dihydro-4H-1,3-oxazin-2-amine;-   (R,Z)-6-(2-(3-(2-amino-5,5-difluoro-4-methyl-5,6-dihydro-4H-1,3-oxazin-4-yl)-4-fluorophenyl)-1-fluorovinyl)nicotinonitrile;-   (R,Z)-5,5-difluoro-4-(2-fluoro-5-(2-fluoro-2-(5-(prop-2-yn-1-yloxy)pyrazin-2-yl)vinyl)phenyl)-4-methyl-5,6-dihydro-4H-1,3-oxazin-2-amine;    or-   (R,Z)-6-(2-(6-(2-amino-5,5-difluoro-4-methyl-5,6-dihydro-4H-1,3-oxazin-4-yl)-5-fluoropyridin-2-yl)-1-fluorovinyl)nicotinonitrile.

Provided herein as an alternative Embodiment 35 is the compound ofEmbodiment 1, or a tautomer thereof, or a pharmaceutically acceptablesalt of said compound or tautomer, selected from

-   (1R,5S,6R)-5-(5-((Z)-2-(5-bromopyridin-2-yl)-2-fluorovinyl)-2-fluorophenyl)-5-(difluoromethyl)-2-oxa-4-azabicyclo[4.1.0]hept-3-en-3-amine;-   6-((Z)-2-(3-((1R,5S,6R)-3-amino-5-(difluoromethyl)-2-oxa-4-azabicyclo[4.1.0]hept-3-en-5-yl)-4-fluorophenyl)-1-fluorovinyl)nicotinonitrile;-   6-((Z)-2-(3-((3R,6R)-5-amino-3,6-dimethyl-6-(trifluoromethyl)-3,6-dihydro-2H-1,4-oxazin-3-yl)-4-fluorophenyl)-1-fluorovinyl)nicotinonitrile;-   5-((Z)-2-(3-((3R,6R)-5-amino-3,6-dimethyl-6-(trifluoromethyl)-3,6-dihydro-2H-1,4-oxazin-3-yl)-4-fluorophenyl)-1-fluorovinyl)pyrazine-2-carbonitrile;-   (2R,5R)-5-(2-fluoro-5-((Z)-2-fluoro-2-(5-(2,2,3,3-tetrafluoropropoxy)pyrazin-2-yl)vinyl)phenyl)-2,5-dimethyl-2-(trifluoromethyl)-5,6-dihydro-2H-1,4-oxazin-3-amine;-   (2R,5R)-5-(2-fluoro-5-((Z)-2-fluoro-2-(5-(prop-2-yn-1-yloxy)pyrazin-2-yl)vinyl)phenyl)-2,5-dimethyl-2-(trifluoromethyl)-5,6-dihydro-2H-1,4-oxazin-3-amine;-   6-((Z)-2-(3-((4R,5R)-2-amino-4-methyl-5-(2,2,2-trifluoroethoxy)-5,6-dihydro-4H-1,3-oxazin-4-yl)-4-fluorophenyl)-1-fluorovinyl)nicotinonitrile;-   (4R,5R)-4-(5-((Z)-2-(5-chloropyrazin-2-yl)-2-fluorovinyl)-2-fluorophenyl)-4-methyl-5-(2,2,2-trifluoroethoxy)-5,6-dihydro-4H-1,3-oxazin-2-amine;-   (4R,5R)-4-(2-fluoro-5-((Z)-2-fluoro-2-(5-(prop-2-yn-1-yloxy)pyrazin-2-yl)vinyl)phenyl)-4-methyl-5-(2,2,2-trifluoroethoxy)-5,6-dihydro-4H-1,3-oxazin-2-amine;-   5-((Z)-2-(3-((4R,5R)-2-amino-4-methyl-5-(2,2,2-trifluoroethoxy)-5,6-dihydro-4H-1,3-oxazin-4-yl)-4-fluorophenyl)-1-fluorovinyl)pyrazine-2-carbonitrile;-   (4R,5R)-4-(5-((Z)-2-(5-(but-2-yn-1-yloxy)pyrazin-2-yl)-2-fluorovinyl)-2-fluorophenyl)-4-methyl-5-(2,2,2-trifluoroethoxy)-5,6-dihydro-4H-1,3-oxazin-2-amine;-   (R,Z)-6-(2-(3-(2-amino-5,5-difluoro-4-methyl-5,6-dihydro-4H-1,3-oxazin-4-yl)-4-fluorophenyl)-1-fluorovinyl)nicotinonitrile;-   (R,Z)-5,5-difluoro-4-(2-fluoro-5-(2-fluoro-2-(5-(prop-2-yn-1-yloxy)pyrazin-2-yl)vinyl)phenyl)-4-methyl-5,6-dihydro-4H-1,3-oxazin-2-amine;-   (R,Z)-6-(2-(6-(2-amino-5,5-difluoro-4-methyl-5,6-dihydro-4H-1,3-oxazin-4-yl)-5-fluoropyridin-2-yl)-1-fluorovinyl)nicotinonitrile;    or-   6-((Z)-2-(6-((3R,6R)-5-amino-3,6-dimethyl-6-(trifluoromethyl)-3,6-dihydro-2H-1,4-oxazin-3-yl)-5-fluoropyridin-2-yl)-1-fluorovinyl)nicotinonitrile.

Provided herein as Embodiment 36 is a pharmaceutical compositioncomprising the compound according to any of Embodiments 1-35, or atautomer thereof, or a pharmaceutically acceptable salt of said compoundor tautomer, and a pharmaceutically acceptable excipient.

Provided herein as Embodiment 37 is a compound according to any one ofEmbodiments 1-35, or a tautomer thereof, or a pharmaceuticallyacceptable salt of said compound or tautomer, or the pharmaceuticalcomposition according to Embodiment 36 for use as a medicament.

Provided herein as Embodiment 38 is a compound according to any one ofEmbodiments 1-35, or a tautomer thereof, or a pharmaceuticallyacceptable salt of said compound or tautomer, or the pharmaceuticalcomposition according to Embodiment 36 for use in reducing beta amyloidpeptide levels in the cerebral spinal fluid of a subject.

Provided herein as Embodiment 39 is a compound according to any one ofEmbodiments 1-35, or a tautomer thereof, or a pharmaceuticallyacceptable salt of said compound or tautomer, or the pharmaceuticalcomposition according to Embodiment 36 for use in treating Alzheimer'sdisease, cognitive impairment, or a combination thereof in a subject.

Provided herein as Embodiment 40 is a compound according to any one ofEmbodiments 1-35, or a tautomer thereof, or a pharmaceuticallyacceptable salt of said compound or tautomer, or the pharmaceuticalcomposition according to Embodiment 36 for use in treating aneurological disorder selected from mild cognitive impairment, Down'ssyndrome, hereditary cerebral hemorrhage with Dutch-type amyloidosis,cerebral amyloid angiopathy, degenerative dementia, dementia associatedwith Parkinson's disease, dementia associated with supranuclear palsy,dementia associated with cortical basal degeneration, diffuse Lewy bodytype of Alzheimer's disease, or a combination thereof in a subject.

Provided herein as Embodiment 41 is a compound according to any one ofEmbodiments 1-35, or a tautomer thereof, or a pharmaceuticallyacceptable salt of said compound or tautomer, or the pharmaceuticalcomposition according to Embodiment 36 for use in reducing formation ofplaque in the brain of a subject.

Provided herein as Embodiment 42 is a use of the compound according toany one of Embodiments 1-35, or a tautomer thereof, or apharmaceutically acceptable salt of said compound or tautomer, or thepharmaceutical composition according to Embodiment 36 in the preparationof a medicament for reducing beta amyloid peptide levels in the cerebralspinal fluid of a subject.

Provided herein as Embodiment 43 is a use of the compound according toany one of Embodiments 1-35, or a tautomer thereof, or apharmaceutically acceptable salt of said compound or tautomer, or thepharmaceutical composition according to Embodiment 36 in the preparationof a medicament for treating Alzheimer's disease, cognitive impairment,or a combination thereof in a subject.

Provided herein as Embodiment 44 is a use of the compound according toany one of Embodiments 1-35, or a tautomer thereof, or apharmaceutically acceptable salt of said compound or tautomer, or thepharmaceutical composition according to Embodiment 36 in the preparationof a medicament for the treatment of a neurological disorder selectedfrom mild cognitive impairment, Down's syndrome, hereditary cerebralhemorrhage with Dutch-type amyloidosis, cerebral amyloid angiopathy,degenerative dementia, dementia associated with Parkinson's disease,dementia associated with supranuclear palsy, dementia associated withcortical basal degeneration, diffuse Lewy body type of Alzheimer'sdisease, or a combination thereof in a subject.

Provided herein as Embodiment 45 is a use of the compound according toany one of Embodiments 1-35, or a tautomer thereof, or apharmaceutically acceptable salt of said compound or tautomer, or thepharmaceutical composition according to Embodiment 36 in the preparationof a medicament for the reduction of formation of plaque in the brain ofa subject.

Provided herein as Embodiment 46 is a method of reducing beta amyloidpeptide levels in the cerebral spinal fluid of a subject in needthereof, the method comprising administering to the subject atherapeutically effective amount of the compound according to any one ofEmbodiments 1-35, or a tautomer thereof, or a pharmaceuticallyacceptable salt of said compound or tautomer.

Provided herein as Embodiment 47 is a method of treating Alzheimer'sdisease, cognitive impairment or a combination thereof in a subject inneed thereof, the method comprising administering to the subject atherapeutically effective amount of the compound according to any one ofEmbodiments 1-35, or a tautomer thereof, or a pharmaceuticallyacceptable salt of said compound or tautomer.

Provided herein as Embodiment 48 is a method of treating a neurologicaldisorder selected from mild cognitive impairment, Down's syndrome,hereditary cerebral hemorrhage with Dutch-type amyloidosis, cerebralamyloid angiopathy, degenerative dementia, dementia associated withParkinson's disease, dementia associated with supranuclear palsy,dementia associated with cortical basal degeneration, diffuse Lewy bodytype of Alzheimer's disease, or a combination thereof in a subject inneed thereof, the method comprising administering to the subject atherapeutically effective amount of the compound according to any one ofEmbodiments 1-35, or a tautomer thereof, or a pharmaceuticallyacceptable salt of said compound or tautomer.

Provided herein as Embodiment 49 is a method of reducing the formationof plaque in the brain of a subject in need thereof, the methodcomprising administering to the subject a therapeutically effectiveamount of a compound according to any one of Embodiments 1-35, or atautomer thereof, or a pharmaceutically acceptable salt of said compoundor tautomer.

If one or more alternative embodiments to a certain embodiment areprovided, a reference to the certain embodiment is also considered to bea reference to any alternative of said certain embodiment provided. Forexample, the reference in Embodiment 36 to, inter alia, Embodiment 35 ismeant to also include a reference to the alternative Embodiment 35provided hereinabove.

The foregoing merely summarizes certain aspects of this disclosure andis not intended, nor should it be construed, as limiting the disclosurein any way.

Definitions

The following definitions are provided to assist in understanding thescope of this disclosure.

Unless otherwise indicated, all numbers expressing quantities ofingredients, reaction conditions, and so forth used in the specificationand claims are to be understood as being modified in all instances bythe term “about.” Accordingly, unless indicated to the contrary, thenumerical parameters set forth in the following specification andattached claims are approximations that may vary depending upon thestandard deviation found in their respective testing measurements.

As used herein, if any variable occurs more than one time in a chemicalformula, its definition on each occurrence is independent of itsdefinition at every other occurrence. If the chemical structure andchemical name conflict, the chemical structure is determinative of theidentity of the compound.

Stereoisomers

The compounds of the present disclosure may contain, for example, doublebonds, one or more assymetric carbon atoms, and bonds with a hinderedrotation, and therefore, may exist as stereoisomers, such as double-bondisomers (i.e., geometric isomers (E/Z)), enantiomers, diastereomers, oratropoisomers. Accordingly, the scope of the instant disclosure is to beunderstood to encompass all possible stereoisomers of the illustratedcompounds including the stereoisomerically pure form (for example,geometrically pure, enantiomerically pure, diastereomerically pure, andatropoisomerically pure) and stereoisomeric mixtures (for example,mixtures of geometric isomers, enantiomers, diastereomers, andatropoisomers) of any chemical structures disclosed herein (in whole orin part). This disclosure also encompasses the pharmaceuticalcompositions comprising stereoisomerically pure forms and the use ofstereoisomerically pure forms of any compounds disclosed herein.Further, this disclosure also encompasses pharmaceutical compositionscomprising mixtures of stereoisomers of any compounds disclosed hereinand the use of said pharmaceutical compositions or mixtures ofstereoisomers. These stereoisomers or mixtures thereof may besynthesized in accordance with methods well known in the art and methodsdisclosed herein. Mixtures of stereoisomers may be resolved usingstandard techniques, such as chiral columns or chiral resolving agents.See, for example, Jacques et al., Enantiomers, Racemates and Resolutions(Wiley-Interscience, New York, 1981); Wilen et al., Tetrahedron 33:2725;Eliel, Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); andWilen, Tables of Resolving Agents and Optical Resolutions, page 268(Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, Ind., 1972).

The term “stereoisomer” or “stereoisomerically pure” compound as usedherein refers to one stereoisomer (for example, geometric isomer,enantiomer, diastereomer and atropoisomer) of a compound that issubstantially free of other stereoisomers of that compound. For example,a stereoisomerically pure compound having one chiral center will besubstantially free of the mirror image enantiomer of the compound and astereoisomerically pure compound having two chiral centers will besubstantially free of other enantiomers or diastereomers of thecompound. A typical stereoisomerically pure compound comprises greaterthan about 80% by weight of one stereoisomer of the compound and lessthan about 20% by weight of other stereoisomers of the compound, greaterthan about 90% by weight of one stereoisomer of the compound and lessthan about 10% by weight of the other stereoisomers of the compound,greater than about 95% by weight of one stereoisomer of the compound andless than about 5% by weight of the other stereoisomers of the compound,or greater than about 97% by weight of one stereoisomer of the compoundand less than about 3% by weight of the other stereoisomers of thecompound. If the stereochemistry of a structure or a portion of astructure is not indicated with, for example, bold or dashed lines, thestructure or portion of the structure is to be interpreted asencompassing all stereoisomers of it. A bond drawn with a wavy lineindicates that both stereoisomers are encompassed. This is not to beconfused with a wavy line drawn perpendicular to a bond which indicatesthe point of attachment of a group to the rest of the molecule.

Tautomers

As known by those skilled in the art, certain compounds disclosed hereinmay exist in one or more tautomeric forms. Because one chemicalstructure may only be used to represent one tautomeric form, it will beunderstood that for convenience, referral to a compound of a givenstructural formula includes other tautomers of said structural formula.For example, the following is illustrative of tautomers of the compoundsof Formula I:

Accordingly, the scope of the instant disclosure is to be understood toencompass all tautomeric forms of the compounds disclosed herein.

Isotopically-Labelled Compounds

Further, the scope of present disclosure includes all pharmaceuticallyacceptable isotopically-labelled compounds of the compounds disclosedherein, such as the compounds of Formula I, wherein one or more atomsare replaced by atoms having the same atomic number, but an atomic massor mass number different from the atomic mass or mass number usuallyfound in nature. Examples of isotopes suitable for inclusion in thecompounds disclosed herein include isotopes of hydrogen, such as ²H and³H, carbon, such as ¹¹C, ¹³C and ¹⁴C, chlorine, such as ³⁶Cl, fluorine,such as ¹⁸F, iodine, such as ¹²³I and ¹²⁵I, nitrogen, such as ¹³N and¹⁵N, oxygen, such as ¹⁵O, ¹⁷O and ¹⁸O, phosphorus, such as ³²P, andsulphur, such as ³⁵S. Certain isotopically-labelled compounds of FormulaI, for example, those incorporating a radioactive isotope, are useful indrug and/or substrate tissue distribution studies. The radioactiveisotopes tritium (³H) and carbon-14 (¹⁴C) are particularly useful forthis purpose in view of their ease of incorporation and ready means ofdetection. Substitution with isotopes such as deuterium (²H) may affordcertain therapeutic advantages resulting from greater metabolicstability, for example, increased in vivo half-life or reduced dosagerequirements, and hence may be advantageous in some circumstances.Substitution with positron emitting isotopes, such as ¹¹C, ¹⁸F, ¹⁵O and¹³N, can be useful in Positron Emission Topography (PET) studies, forexample, for examining target occupancy. Isotopically-labelled compoundsof the compounds disclosed herein can generally be prepared byconventional techniques known to those skilled in the art or byprocesses analogous to those described in the accompanying GeneralSynthetic Schemes and Examples using an appropriateisotopically-labelled reagents in place of the non-labelled reagentpreviously employed.

Solvates

As discussed above, the compounds disclosed herein and thestereoisomers, tautomers and isotopically-labelled forms thereof or apharmaceutically acceptable salt of any of the foregoing may exist insolvated or unsolvated forms.

The term “solvate” as used herein refers to a molecular complexcomprising a compound or a pharmaceutically acceptable salt thereof asdescribed herein and a stoichiometric or non-stoichiometric amount ofone or more pharmaceutically acceptable solvent molecules. If thesolvent is water, the solvate is referred to as a “hydrate.”

Accordingly, the scope of the instant disclosure is to be understood toencompass all solvents of the compounds disclosed herein and thestereoisomers, tautomers and isotopically-labelled forms thereof or apharmaceutically acceptable salt of any of the foregoing.

Amorphous and Crystalline Forms

In certain embodiments, the compounds described herein and thestereoisomers, tautomers, isotopically-labelled forms thereof orpharmaceutically acceptable salts of any of the foregoing or solvates ofany of the foregoing may exist in different forms, such as amorphousforms and crystalline forms (polymorphs). Accordingly, the scope of theinstant disclosure is to be understood to encompass all such forms.

Miscellaneous Definitions

This section will define additional terms used to describe the scope ofthe compounds, compositions and uses disclosed herein.

The term “C_(x-y)alkoxy” as used herein refers to a radical —OR where Rrepresents a C_(x-y)alkyl group as defined herein. The C_(x-y)alkylgroup contains, for example, 1 to 6 carbon atoms (C₁₋₆alkyl).Accordingly, a C₁₋₆alkoxy group refers to a —OC₁₋₆alkyl group.Representative examples of C₁₋₆alkoxy include, but are not limited to,methoxy, ethoxy, propoxy, and butoxy.

The term “C_(x-y)alkyl” as used herein refers to a straight or branchedchain hydrocarbon containing from x to y carbon atoms, for example, 1 to4 (C₁₋₄alkyl) and 1 to 6 (C₁₋₆alkyl) carbon atoms. Representativeexamples of C₁₋₄alkyl include, but are not limited to, methyl, ethyl,n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, and tert-butyl.Representative examples of C₁₋₆alkyl include, but are not limited to,methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl,tert-butyl, n-pentyl, isopentyl, neopentyl, and n-hexyl.

The term “C₃₋₆cycloalkyl” as used herein refers to a saturatedcarbocyclic molecule wherein the cyclic framework has 3 to 6 carbons.Representative examples of C₃₋₆cycloalkyl include, but are not limitedto, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. TheC₃₋₆cycloalkyl may be fused to another ring, such as a5,6-dihydro-4H-1,3-oxazin-2-amine, to form a bicyclic ring system, forexample, a 2-oxa-4-azabicyclo[4.1.0]hept-3-en-3-amine,2-oxa-4-azabicyclo[4.2.0]oct-3-en-3-amine,4,4a,5,6,7,7a-hexahydrocyclopenta[e][1,3]oxazin-2-amine, and4a,5,6,7,8,8a-hexahydro-4H-benzo[e][1,3]oxazin-2-amine.

The term “halogen” as used herein refers to —F, —Cl, —Br, or —I.

The term “6-membered nitrogen-containing heteroaryl” as used hereinrefers to a heteroaryl ring having 6 ring atoms selected from carbon ornitrogen, wherein one to four of the ring atoms are nitrogen. Examplesof 6-membered nitrogen-containing heteroaryls include, but are notlimited to, pyridyl, pyrazinyl, pyrimidinyl, and pyridazinyl.

The term “pharmaceutically acceptable” as used herein refers togenerally recognized for use in subjects, particularly in humans.

The term “pharmaceutically acceptable salt” as used herein refers to asalt of a compound that is pharmaceutically acceptable and thatpossesses the desired pharmacological activity of the parent compound.Such salts include: (1) acid addition salts, formed with inorganic acidssuch as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,phosphoric acid, and the like; or formed with organic acids such asacetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid,glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid,malic acid, maleic acid, fumaric acid, tartaric acid, citric acid,benzoic acid, 3-(4-hydroxybenzoyl) benzoic acid, cinnamic acid, mandelicacid, methanesulfonic acid, and the like; or (2) salts formed when anacidic proton present in the parent compound either is replaced by ametal ion, for example, an alkali metal ion, an alkaline earth ion, oran aluminum ion; or coordinates with an organic base such asethanolamine, diethanolamine, triethanolamine, N-methylglucamine,dicyclohexylamine, and the like. Additional examples of such salts canbe found in Berge et al., J. Pharm. Sci. 66(1):1-19 (1977). See alsoStahl et al., Pharmaceutical Salts: Properties, Selection, and Use,2^(nd) Revised Edition (2011).

The term “pharmaceutically acceptable excipient” as used herein refersto a broad range of ingredients that may be combined with a compound orsalt disclosed herein to prepare a pharmaceutical composition orformulation. Typically, excipients include, but are not limited to,diluents, colorants, vehicles, anti-adherants, glidants, disintegrants,flavoring agents, coatings, binders, sweeteners, lubricants, sorbents,preservatives, and the like.

The term “subject” as used herein refers to humans and mammals,including, but not limited to, primates, cows, sheep, goats, horses,dogs, cats, rabbits, rats, and mice. In one embodiment the subject is ahuman.

The term “treating” as used herein refers not only to treating a subjectto relieve the subject of one or more signs and symptoms of a disease orcondition or to eliminate one or more such signs and symptoms, but alsoto prophylactically treating an asymptomatic subject to prevent theonset of the disease or condition or preventing, slowing or reversingthe progression of the disease or condition.

The term “therapeutically effective amount” as used herein refers tothat amount of a compound disclosed herein that will elicit thebiological or medical response of a tissue, a system, or subject that isbeing sought by a researcher, veterinarian, medical doctor or otherclinician. The term also encompasses the amount of compound disclosedherein that will prevent or reduce the risk of occurrence of thebiological or medical event that is sought to be prevented in a tissue,a system, or subject by a researcher, veterinarian, medical doctor orother clinician.

General Synthetic Procedures

The compounds provided herein can be synthesized according to theprocedures described in this and the following sections. The syntheticmethods described herein are merely exemplary, and the compoundsdisclosed herein may also be synthesized by alternate routes utilizingalternative synthetic strategies, as appreciated by persons of ordinaryskill in the art. It should be appreciated that the general syntheticprocedures and specific examples provided herein are illustrative onlyand should not be construed as limiting the scope of the presentdisclosure in any manner.

Generally, the compounds of Formula I can be synthesized according tothe following schemes. Any variables used in the following schemes arethe variables as defined for Formula I, unless otherwise noted. Allstarting materials are either commercially available, for example, fromSigma-Aldrich Chemical Company, Inc., St. Louis, Mo., USA, or known inthe art and may be synthesized by employing known procedures usingordinary skill. Starting material may also be synthesized via theprocedures disclosed herein.

The alkene iv, wherein R⁶ is F, may be synthesized as shown in Scheme 1.The starting material R⁷—Br is reacted with ethyl2-bromo-2,2-difluoroacetate to give ester i. Ester i is then reduced,for example, with sodium borohydride, to give alcohol ii. The OH groupof alcohol ii is then transformed into an iodo group yielding compoundiii by transforming the OH group in a leaving group followed by anucleophilic substitution, for example, by reacting alcohol ii withtriflic anhydride in presence of a base, such as pyridine, followed byreaction with I⁻, sourced from, for example, sodium iodide. Alkene iv isthen obtained by reacting compound iii with a base, such as potassiumtert-butoxide.

Sulfone viii, wherein R⁶ is F, may be synthesized as shown in Scheme 2.First, the OH group of R⁷CH₂OH is transformed into a leaving group, forexample by reacting R⁷CH₂OH with methane sulfonyl chloride in presenceof a base, such as trimethylamine, to give compound v. Then, compound vis reacted with 3,5-bis(trifluoromethyl)benzenethiol in presence of abase, such as sodium hydroxide, to give compound vi. Alternatively,R⁷CH₂X, wherein X is Cl, Br, or I, may be directly reacted with3,5-bis(trifluoromethyl)benzenethiol in presence of a base, such aspotassium carbonate, to give compound vi. The sulfone vii is obtained byreacting compound vi under oxidizing conditions using, for example,hydrogen peroxide. Sulfone viii, wherein R⁶ is F, was obtained reactingsulfone vii with an electrophilic fluorination agent, such asN-fluorodibenzenesulfonimide, in presence of a base, such as lithiumdiisopropylamide.

The final compound xii, wherein R⁶ is H or F, may be synthesized asshown in Scheme 3. First, the free amino group of compound ix, wherein Zis Cl, Br or I, is suitably protected, for example by reaction withdi-tert-butyl dicarbonate in presence of a base, such asN,N-diisopropylethylamine (Hünig's base). The suitably protectedcompound x is then transformed into boronic acid xi, for example byreacting bis(pinacolato)diboron in presence of a base, such as potassiumacetate, and a suitable palladium catalyst, such[1,1′-bis(diphenylphosphino)ferrocene]-dichloropalladium(II). The finalcompound xii is obtained by reacting boronic acid xi with compound iv,wherein R⁶ is H or F, under Suzuki conditions, in presence of, forexample,bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)-dichloropalladium(II)and a base, such as potassium phosphate, followed by a deprotection ofthe amino group by reacting the Suzuki product with, for example,trifluoroacetic acid, if a di-BOC protecting strategy was employed.

The final compound xii, wherein one of R⁶ and R⁷ is either H or F, maybe synthesized as shown in Scheme 4. First, the free amino group ofcompound ix, wherein X is Cl, Br, or I, is suitably protected, forexample by reaction with benzoic anhydride in presence of a base, suchas trimethylamine. The suitably protected compound x is then transformedinto alkene xiii by reacting compound x with, for example, potassiumvinyltrifluoroborate in presence of a base, such as potassium acetate,and a suitable palladium catalyst, such asbis(di-tert-butyl(4-dimethylaminophenyl)phosphine)-dichloropalladium(II).Aldehyde xiv is obtained by subjecting alkene xiii to oxidizingconditions using, for example osmiumtetroxide,4-methylmorpholine-N-oxide, and potassium periodate. Aldehyde xiv isthen reacted with compound viii in presence of a base, such as lithiumbis(trimethylsilyl)amide, followed by conditions removing the protectinggroup(s) from the amino group using, for example,1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), if a benzoyl protectingstrategy was employed, giving final compound xii.

The final compounds xv and xvi, wherein Z is H or F, may be synthesizedas shown in Scheme 5. The suitably protected compound xi is the coupledto a suitable vinyl iodide, wherein Z is F or H, for example, inpresence of a base, such as potassium acetate, and a suitable palladiumcatalyst, such asbis(di-tert-butyl(4-dimethylaminophenyl)phosphine)-dichloropalladium(II).Following conditions removing the protecting group(s) from the aminogroup using, for example, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), if abenzoyl protecting strategy was employed, final compound(s) xv and/orxvi may be obtained.

As can be appreciated by the skilled artisan, the above syntheticschemes and representative examples are not intended to comprise acomprehensive list of all means by which the compounds described andclaimed in this application may be synthesized. Further methods will beevident to those of ordinary skill in the art. Additionally, the varioussynthetic steps described above may be performed in an alternatesequence or order to give the desired compounds.

For example, in these procedures, the steps may be preceded, orfollowed, by additional protection/deprotection steps as necessary.Particularly, if one or more functional groups, for example carboxy,hydroxy, amino, or mercapto groups, are or need to be protected inpreparing the compounds disclosed herein, because they are not intendedto take part in a specific reaction or chemical transformation, variousknown conventional protecting groups may be used. For example,protecting groups typically utilized in the synthesis of natural andsynthetic compounds, including peptides, nucleic acids, derivativesthereof and sugars, having multiple reactive centers, chiral centers andother sites potentially susceptible to the reaction reagents and/orconditions, may be used.

Synthetic chemistry transformations and protecting group methodologies(protection and deprotection) useful in synthesizing the compoundsdescribed herein are known in the art and include, for example, thosesuch as described in R. Larock, Comprehensive Organic Transformations,VCH Publishers (1989); T. W. Greene and P. G. M. Wuts, Protective Groupsin Organic Synthesis, 3^(rd) edition, John Wiley and Sons (1999); L.Fieser and M. Fieser, Fieser and Fieser's Reagents for OrganicSynthesis, John Wiley and Sons (1994); A. Katritzky and A. Pozharski,Handbook of Heterocyclic Chemistry, 2^(nd) edition (2001); M. Bodanszky,A. Bodanszky, The Practice of Peptide Synthesis, Springer-Verlag, BerlinHeidelberg (1984); J. Seyden-Penne, Reductions by the Alumino- andBorohydrides in Organic Synthesis, 2^(nd) edition, Wiley-VCH, (1997);and L. Paquette, editor, Encyclopedia of Reagents for Organic Synthesis,John Wiley and Sons (1995).

All synthetic procedures described herein can be carried out under knownreaction conditions, advantageously under those described herein, eitherin the absence or in the presence (usually) of solvents. As appreciatedby those of ordinary skill in the art, the solvents should be inert withrespect to, and should be able to dissolve, the starting materials andother reagents used. Solvents should be able to partially or whollysolubilize the reactants in the absence or presence of catalysts,condensing agents or neutralizing agents, for example ion exchangers,typically cation exchangers for example in the H⁺ form. The ability ofthe solvent to allow and/or influence the progress or rate of thereaction is generally dependent on the type and properties of thesolvent(s), the reaction conditions including temperature, pressure,atmospheric conditions such as in an inert atmosphere under argon ornitrogen, and concentration, and of the reactants themselves.

Suitable solvents for conducting reactions to synthesize the compoundsprovided herein include, but are not limited to, water; esters,including lower alkyl-lower alkanoates, for example, EtOAc; ethersincluding aliphatic ethers, for example, Et₂O and ethylene glycoldimethylether or cyclic ethers, for example, THF; liquid aromatichydrocarbons, for example, benzene, toluene and xylene; alcohols, forexample, MeOH, EtOH, 1-propanol, iPrOH, n- and t-butanol; nitriles, forexample, CH₃CN; halogenated hydrocarbons, for example, CH₂Cl₂, CHCl₃ andCCl₄; acid amides, for example, DMF; sulfoxides, for example, DMSO;bases, including heterocyclic nitrogen bases, for example, pyridine;carboxylic acids, for example, lower alkanecarboxylic acids, forexample, AcOH; inorganic acids, for example, HCl, HBr, HF, and H₂SO₄;carboxylic acid anhydrides, for example, lower alkane acid anhydrides,for example, acetic anhydride; cyclic, linear, or branched hydrocarbons,for example, cyclohexane, hexane, pentane, and isopentane; and mixturesof any of these solvents, such as purely organic solvent combinations,or water-containing solvent combinations, for example, aqueoussolutions. These solvents and solvent mixtures may also be used in“working-up” the reaction as well as in processing the reaction and/orisolating the reaction product(s), such as in chromatography.

Purification methods are known in the art and include, for example,crystallization, chromatography (for example, liquid and gas phase),extraction, distillation, trituration, and reverse phase HPLC. Reactionsconditions such as temperature, duration, pressure, and atmosphere(inert gas, ambient) are known in the art and may be adjusted asappropriate for the reaction.

The disclosure further encompasses “intermediate” compounds, includingstructures produced from the synthetic procedures described, whetherisolated or generated in-situ and not isolated, prior to obtaining thefinally desired compound. Structures resulting from carrying out stepsfrom a transient starting material, structures resulting from divergencefrom the described method(s) at any stage, and structures formingstarting materials under the reaction conditions are all “intermediates”included in the scope of this disclosure.

Further, processes for making and further reacting these intermediatesare also understood to be encompassed in the scope of this disclosure.

Also provided herein are new starting materials and/or intermediates, aswell as processes for the preparation thereof. In select embodiments,such starting materials are used and reaction conditions so selected asto obtain the desired compound(s). Starting materials are either known,commercially available, or can be synthesized in analogy to or accordingto methods that are known in the art. Many starting materials may beprepared according to known processes and, in particular, can beprepared using processes described in the examples. In synthesizingstarting materials, functional groups may be protected with suitableprotecting groups when necessary. Protecting groups, their introductionand removal are described above.

EXAMPLES

This section provides specific examples of compounds of Formula I andmethods of making the same.

List of Abbreviations

TABLE 1 ACN acetonitrile (BPin)₂ bis(pinacolatodiboron) Boctert-butylcarbonyl Boc₂O di-tert-butyldicarbonate Bz₂O benzoyl anhydrideDBU 1,8-diazabicyclo[5.4.0]undec-7-ene DCM dichloromethane DMAPN,N-dimethylaminopyridine DMA dimethylacetamide DMF dimethylformamideDMSO dichloromethane EtOH ethanol LDA lithium diisopropylamide LiHMDSlithium (bistrimethylsilylamide) mCPBA meta-chloroperoxybenzoic acidNFSI N-fluorodibenzenesulfonimide NMO N-methylmorpholine N-oxidePd(AmPhos)Cl₂ bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) Pd₂(dba)₃tris(dibenzylideneacetone)dipalladium(0) Pd(dppf)Cl₂ [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) p-TSA4-toluenesulfonic acid S-Phos2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl SEM[2-(trimethylsilyl)ethoxy]methyl SEMCl(2-chloromethoxyethyl)trimethylsilane TFA trifluoroacetic acid Tf₂Otrifluoromethanesulfonic anhydride THF tetrahydrofuran TLC thin layerchromatography

General Analytical and Purification Methods

Provided in this section are descriptions of the general analytical andpurification methods used to prepare the specific compounds providedherein.

Chromatography:

Unless otherwise indicated, crude product-containing residues werepurified by passing the crude material or concentrate through either aBiotage or Isco brand silica gel column (pre-packed or individuallypacked with SiO₂) and eluting the product off the column with a solventgradient as indicated. For example a description of (330 g SiO₂, 0-40%EtOAc/hexane) means the product was obtained by elution from the columnpacked with 330 grams of silica, with a solvent gradient of 0% to 40%EtOAc in hexane.

Preparative HPLC Method:

Where so indicated, the compounds described herein were purified viareverse phase HPLC using one of the following instruments: Shimadzu,Varian, Gilson; utilizing one of the following two HPLC columns: (a) aPhenomenex Luna or (b) a Gemini column (5 micron or 10 micron, C18,150×50 mm)

A typical run through the instrument included: eluting at 45 mL/min witha linear gradient of 10% (v/v) to 100% MeCN (0.1% v/v TFA) in water(0.1% TFA) over 10 minutes; conditions can be varied to achieve optimalseparations.

Proton NMR Spectra:

Unless otherwise indicated, all ¹H NMR spectra were collected on aBruker NMR instrument at 300 MHz or 400 MHz. Where so characterized, allobserved protons are reported as parts-per-million (ppm) downfield fromtetramethylsilane (TMS) or other internal reference in the appropriatesolvent indicated.

¹⁹F NMR Spectra:

Unless otherwise indicated, all ¹⁹F NMR spectra were collected on aBruker NMR instrument at 376 MHz. All observed protons are reported asparts-per-million (ppm) downfield.

Mass Spectra (MS)

Unless otherwise indicated, all mass spectral data for startingmaterials, intermediates and/or exemplary compounds are reported asmass/charge (m/z), having an (M+H⁺) molecular ion. The molecular ionreported was obtained by electrospray detection method (commonlyreferred to as an ESI MS) utilizing a PE SCIEX API 150EX MS instrumentor an Agilent 1100 series LC/MSD system. Compounds having an isotopicatom, such as bromine and the like, are generally reported according tothe detected isotopic pattern, as appreciated by those skilled in theart.

Compound Names

The compounds disclosed and described herein have been named usingeither (1) the naming convention provided with Chem-Draw Ultra 12.0.3.software, available in Chem Office, or (2) by the ISIS database software(Advanced Chemistry Design Labs or ACD software).

Specific Examples

Provided in this section are the procedures to synthesize specificexamples of the compounds provided herein. All starting materials areeither commercially available from Sigma-Aldrich Chemical Company, Inc.,St. Louis, Mo., USA, unless otherwise noted, or known in the art and maybe synthesized by employing known procedures using ordinary skill.

Intermediates Intermediate 1:2-(((3,5-bis(trifluoromethyl)phenyl)sulfonyl)fluoromethyl)-5-bromopyridine

Preparation of2-(((3,5-bis(trifluoromethyl)phenyl)thio)methyl)-5-bromopyridine (1b)

Methane sulfonyl chloride (5.3 mL, 69.1 mmol) was added dropwise to anice cold solution of 5-bromo-2-hydroxymethylpyridine (Sigma-AldrichChemical Company, Inc., St. Louis, Mo., USA) (10.0 g, 53.2 mmol) and TEA(11.1 mL, 80.0 mmol) in THF (150 mL). The mixture was stirred for 1hour. Water was then added and the product was extracted into EtOAc(2×). The combined organic layers were dried over anhydrous MgSO₄,filtered, and concentrated in vacuo to give mesylate 1a as an oil.

3,5-Bis-trifluoromethyl benzenethiol (Sigma-Aldrich, 8.9 mL, 53.2 mmol)was dissolved in MeOH (150 mL). Aqueous sodium hydroxide (2 N, 31.9 mL)was added and then the mixture was stirred for 5 minutes. The mesylate1a was added as a suspension in MeOH (40 mL) and the mixture was stirredfor 1 hour at room temperature before the MeOH was removed in vacuo. Theresulting residue was partitioned between water and EtOAc, the layerswere separated, and the aqueous layer was extracted with EtOAc. Thecombined extracts were dried over anhydrous MgSO₄, filtered, andconcentrated in vacuo to give2-(((3,5-bis(trifluoromethyl)phenyl)thio)methyl)-5-bromopyridine (1b)(22.3 g, 101% yield) as an oil. MS m/z=416/418 [M+H]⁻. ¹H NMR (400 MHz,CDCl₃) δ ppm 8.59 (s, 1H) 7.73-7.79 (m, 3H) 7.63 (s, 1H) 7.26 (d, J=8.02Hz, 1H) 4.29 (s, 2H).

Preparation of2-(((3,5-bis(trifluoromethyl)phenyl)sulfonyl)methyl)-5-bromopyridine(1c)

A 100 mL 2-necked flask was charged with2-(((3,5-bis(trifluoromethyl)phenyl)thio)methyl)-5-bromopyridine (1b)(1.8 g, 4.3 mmol), placed under argon atmosphere, and dissolved in CH₃CN(20 mL). The mixture was cooled to 4° C. internal temperature using anice water bath, and then hydrogen peroxide urea adduct (1.0 g, 11 mmol)and TFAA (2.3 g, 11 mmol) were added. This mixture was stirred withwarming to room temperature for 3 hours. In a separate flask, hydrogenperoxide urea adduct (1.0 g) was suspended in CN₃CN (20 mL) and TFAA(2.3 g) was added. This mixture was stirred until all the peroxidecomplex went into solution (about 30 minutes) and then it was added tothe reaction mixture. The reaction was stirred for 1 hour and thentransferred to a separatory funnel. EtOAc and sat'd aqueous sodiumbicarbonate solution were added. The layers were mixed and thenseparated. The organic layer was washed with saturated aqueous sodiumthiosulfate until peroxide test strips showed negative for peroxide. Theorganic solution was dried over MgSO₄, filtered, and then concentratedin vacuo to give a mixture of the desired sulfone product and itscorresponding N-oxide, which was taken directly to the next step.

A mixture of iron (0) powder (0.96 g, 17 mmol), acetic acid (2.5 mL, 43mmol), and the material generated in the first step in EtOH (25 mL) washeated to 80° C. for 3 hours. The solution was then filtered through apad of celite while hot and the filtrate was concentrated in vacuo. Theresidue was partitioned between EtOAc and saturated aqueous sodiumbicarbonate, the layers were separated, and the organic layer was washedwith saturated aqueous sodium bicarbonate (2×), dried over MgSO₄,filtered, and concentrated in vacuo. The resulting solid wasrecrystallized from 1:1 EtOAc/heptane to give2-(((3,5-bis(trifluoromethyl)phenyl)sulfonyl)methyl)-5-bromopyridine(1c) (1.1 g, 58% yield for 2 steps) as a white solid. MS m/z=448/450[M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ ppm 8.61 (s, 1H) 8.54 (d, J=2.15 Hz,1H) 8.26 (s, 2H) 8.14 (dd, J=8.50, 2.35 Hz, 1H) 7.46 (d, J=8.41 Hz, 1H)5.14 (s, 2H).

Preparation of2-(((3,5-bis(trifluoromethyl)phenyl)sulfonyl)fluoromethyl)-5-bromopyridine(1)

LDA (2.0 M solution in THF/heptane/ethylbenzene, 4.4 mL, 8.8 mmol) wasadded dropwise to a solution of2-(((3,5-bis(trifluoromethyl)phenyl)sulfonyl)methyl)-5-bromopyridine(1c) (3.79 g, 8.46 mmol) in THF (30 mL) at −78° C. This mixture was thenstirred for 15 minutes before N-fluorobenzenesulfonimide (2.80 g, 8.88mmol) was added in one portion. The ice bath was removed and the mixturewas allowed to warm to room temperature and stir for 30 minutes. Waterwas added and the product was extracted into DCM. The resulting solidwas recrystallized once from DCM to give 2.0 g product, and then theremaining material was recrystallized from 1:1 EtOAc/heptane to give anadditional 0.6 g of product. Together, the recrystallizations gave 2.6 g(65% yield) of2-(((3,5-bis(trifluoromethyl)phenyl)sulfonyl)fluoromethyl)-5-bromopyridine(1) as a white solid. MS m/z=466/468 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δppm 8.73 (d, J=2.15 Hz, 1H) 8.34 (s, 2H) 8.23 (s, 1H) 7.99 (dd, J=8.16,2.35 Hz, 1H) 7.50 (d, J=8.22 Hz, 1H) 6.22 (d, J=45.97 Hz, 1H).

Intermediate 2: (Z)-5-chloro-2-(1-fluoro-2-iodovinyl)pyridine

Preparation of ethyl 2-(5-chloropyridin-2-yl)-2,2-difluoroacetate (2a)

Ethyl 2-bromo-2,2-difluoroacetate (105 g, 520 mmol) was added slowly toa suspension of copper (0) powder (66.0 g, 1040 mmol) in DMSO (1.2 L)under nitrogen atmosphere at room temperature. The reaction mixture wasstirred at room temperature for 1 hour and 2-bromo-5-chloropyridine(Shanghai Fchemicals Technology Co., Ltd., Shanghai, China) (50.0 g, 260mmol) was added in one portion. The reaction mixture was stirred at roomtemperature for 12 hours. It was filtered through a pad of celite andthe filtrate was partitioned between ethyl acetate (1 L) and sat'daqueous ammonium chloride (100 mL) and water (100 mL). The organic layerwas separated and the aqueous layer was extracted with ethyl acetate(2×100 mL). The combined organic solution was washed with water (2×100mL), dried over Na₂SO₄ and concentrated. Purification of the residue bysilica gel chromatography (0 to 10% ethyl acetate in hexanes) gave 2a(60 g, 64% yield) as a clear liquid. MS (ESI+ve ion) m/z: [M+1]=236.0.¹H NMR (400 MHz, Chloroform-d) δ 8.63-8.59 (m, 1H), 7.85 (dt, J=8.4, 1.6Hz, 1H), 7.70 (dt, J=8.4, 0.9 Hz, 1H), 4.11 (q, J=7.1, 1.0 Hz, 2H), 1.26(t, J=7.1, 1.0 Hz, 3H).

Preparation of 2-(5-chloropyridin-2-yl)-2,2-difluoroethan-1-ol (2b)

To a solution of 2a (47.0 g, 199 mmol) in ethanol (600 mL) at 0° C. wasadded sodium borohydride (7.5 g, 199 mmol) portion-wise. The reactionmixture was stirred at room temperature for 1 hour. It was quenched withwater (500 mL) and concentrated under reduced pressure. The crudematerial was diluted with water (500 mL) and extracted with ethylacetate (2×500 mL). The combined organic extracts were dried over Na₂SO₄and concentrated. Purification of the residue by silica gelchromatography (0 to 10% ethyl acetate in hexanes) gave 2b (35 g, 91%yield) as a light yellow solid. MS (ESI+ve ion) m/z: [M+1]=194.2. ¹H NMR(400 MHz, Chloroform-d) δ 8.64-8.58 (m, 1H), 7.86 (dd, J=8.4, 2.4 Hz,1H), 7.70 (dt, J=8.5, 1.5 Hz, 1H), 4.24 (t, J=12.4 Hz, 2H). Note: OHproton was not observed.

Preparation of 5-chloro-2-(1,1-difluoro-2-iodoethyl)pyridine (2c)

To a solution of 2b (31 g, 160 mmol) in DCM (500 mL) at 0° C. was addedtriethylamine (49.1 mL, 352 mmol) followed by dropwise addition ofmethanesulfonyl chloride (23.7 mL, 304 mmol). The reaction mixture wasstirred at room temperature for 1 hour. The reaction mixture was dilutedwith water (500 mL) and extracted with DCM (2×500 mL). The combinedorganic extracts were washed with brine (250 mL), dried over Na₂SO₄ andconcentrated under reduced pressure. The residue was dissolved inN,N-dimethyl acetamide (600 mL) and sodium iodide (96 g, 641 mmol) addedin portion-wise manner. The reaction mixture was heated at 110° C. for36 hours. It was cooled to room temperature, diluted with water (500mL), and extracted with ethyl acetate (2×500 mL). The combined organiclayers were washed with brine (500 mL), dried over Na₂SO₄ andconcentrated under reduced pressure. The residue was purified by silicagel chromatography (0 to 10% ethyl acetate in hexanes) to give 2c (30 g,60% yield) as a brown solid. MS (ESI+ve ion) m/z: [M+1]=303.9. ¹H NMR(400 MHz, Chloroform-d) δ 8.59 (s, 1H), 7.87-7.84 (m, 1H), 7.27 (d,J=2.0 Hz, 1H), 4.27 (t, J=12.4 Hz, 2H).

Preparation of (Z)-5-chloro-2-(1-fluoro-2-iodovinyl)pyridine (2)

To a solution of 2c (30 g, 99 mmol) in DMSO (50 mL, 1.66 mL/g) was addeda solution of KOH (19.4 g, 346 mmol) in water (50 mL) dropwise at 0° C.The reaction mixture was stirred at room temperature for 10 hours. Itwas diluted with water (150 mL) and stirred for 15 minutes. Theprecipitated solids were collected by filtration, washed with water(2×100 mL), and dried to afford(Z)-5-chloro-2-(1-fluoro-2-iodovinyl)pyridine (2) (24.7 g, 87% yield) asa white crystalline solid. MS (ESI+ve ion) m/z: [M+1]=284.0. ¹H NMR (400MHz, Chloroform-d) δ 8.54-8.51 (m, 1H), 7.74 (dd, J=8.5, 2.4 Hz, 1H),7.50 (ddd, J=8.5, 1.8, 0.8 Hz, 1H), 6.94 (d, J=34.3 Hz, 1H).

Intermediate 3: (Z)-6-(1-fluoro-2-iodovinyl)nicotinonitrile

Preparation of ethyl 2-(5-cyanopyridin-2-yl)-2,2-difluoroacetate (3a)

To a suspension of copper (0) powder (Spectrochem PVT. LTD., Mumbai,India) (413 g, 6560 mmol) in dimethyl sulfoxide (6 L) was added ethyl2-bromo-2,2-difluoroacetate (Matrix Scientific, Columbia, S.C., USA)(665 g, 3280 mmol) dropwise under nitrogen atmosphere at roomtemperature. The reaction mixture was stirred at room temperature for 1hour and 2-bromo-5-cyanopyridine (Sigma-Aldrich, St. Louis, Mo., USA)(300 g, 1640 mmol) was added in portion-wise manner. The reactionmixture was stirred at room temperature for 12 hours. It was filteredthrough a pad of celite and the filtrate was partitioned between ethylacetate (3 L) and sat'd aqueous ammonium chloride (2.5 mL). The organiclayer was separated and the aqueous layer was extracted with ethylacetate (2×2 L). The combined organic layers were washed with water (2×2L), dried over Na₂SO₄ and concentrated under reduced pressure. Theresidue was purified by silica gel chromatography (0 to 10% ethylacetate in hexanes) to give 3a (320 g, 86% yield) as a colourless oil.MS (ESI+ve ion) m/z: [M+1]=227.1. ¹H NMR (400 MHz, Chloroform-d) δ 8.93(d, J=2.0 Hz, 1H), 8.18 (dd, J=8.2, 2.1 Hz, 1H), 7.90 (dd, J=8.1, 1.0Hz, 1H), 4.39 (q, J=7.1 Hz, 2H), 1.34 (t, J=7.1 Hz, 3H).

Preparation of 6-(1,1-difluoro-2-hydroxyethyl)nicotinonitrile (3b)

To a solution of 3a (105 g, 464 mmol) in THF (1.5 L) was added sodiumborohydride (10.5 g, 279 mmol) portion-wise at −20° C. The reactionmixture was stirred at −20° C. for 30 minutes and methanol (525 mL) wasadded dropwise at −20° C. The reaction mixture was stirred at −20° C.for 1 hour, and quenched with water (500 mL). It was concentrated underreduced pressure. The residue was diluted with water (0.5 L) andextracted with ethyl acetate (2×1 L). The combined organic solution wasdried over Na₂SO₄ and concentrated. The residue was purified by silicagel chromatography (0 to 25% ethyl acetate in hexanes) to provide 3b(43.0 g, 50% yield) as a light-yellow solid. MS (ESI+ve ion) m/z:[M+1]=185.1. ¹H NMR (400 MHz, Chloroform-d) δ 8.97-8.90 (m, 1H), 8.18(dd, J=8.2, 2.1 Hz, 1H), 7.89 (dd, J=8.3, 0.9 Hz, 1H), 4.29 (t, J=12.4Hz, 2H). Note: OH proton was not observed.

Preparation of 6-(1,1-difluoro-2-iodoethyl)nicotinonitrile (3c)

To a solution of 3b (87 g, 472 mmol) in acetonitrile (1.3 L) was addedpyridine (74.7 g, 945 mmol) followed by dropwise addition oftrifluoromethanesulfonic anhydride (Sigma-Aldrich, St. Louis, Mo., USA)(240 g, 850 mmol) at −10° C. under nitrogen atmosphere. The reactionmixture was stirred at room temperature for 5 hours. It was cooled to 0°C. and sodium iodide (354 g, 2362 mmol) was added in portion-wisemanner. The reaction mixture was heated at 60° C. for 2 hours. It wascooled to room temperature, diluted with water (2 L) and extracted withethyl acetate (3×3 L). The combined organic solution was dried overNa₂SO₄ and concentrated under reduced pressure. The crude material waspurified on a silica gel column (0 to 10% ethyl acetate in hexanes) toafford 3c (107 g, 77% yield) as a light-yellow solid. MS (ESI+ve ion)m/z: [M+1]=295.0. ¹H NMR (400 MHz, Chloroform-d) δ 8.95 (s, 1H),8.17-8.14 (m, 1H), 7.87-7.85 (d, J=8.0 Hz, 1H), 3.97 (t, J=14.4 Hz, 2H).

Preparation of 6-(1,1-difluoro-2-iodoethyl)nicotinonitrile (3)

To a solution of 3c (58 g, 197 mmol) in THF (580 mL) was added potassiumtert-butoxide (26.6 g, 237 mmol) portionwise at 0° C. The reactionmixture was stirred at 0° C. for 2 hours, then quenched with sat'd NH₄Cl(100 mL) and water (100 mL). It was extracted with ethyl acetate (3×700mL). The combined organic extracts were dried over Na₂SO₄ andconcentrated. Purification of the residue via silica gel chromatography(0 to 5% ethyl acetate in hexanes) gave6-(1,1-difluoro-2-iodoethyl)nicotinonitrile (3) (33 g, 61% yield) as alight yellow solid. MS (ESI+ve ion) m/z: [M+1]=274.9. ¹H NMR (400 MHz,DMSO-d₆) δ 9.04 (dd, J=2.1, 1.0 Hz, 1H), 8.45 (dd, J=8.3, 2.1 Hz, 1H),7.81 (dt, J=8.3, 1.1 Hz, 1H), 7.42 (d, J=36.4 Hz, 1H).

Intermediate 4: (Z)-2-chloro-5-(1-fluoro-2-iodovinyl)pyrazine

Preparation of ethyl 2-(5-chloropyrazin-2-yl)-2,2-difluoroacetate (4a)

To a suspension of copper (0) powder (244 g, 3880 mmol) in DMSO (5 L)was added ethyl 2-bromo-2,2-difluoroacetate (394 g, 1940 mmol) at roomtemperature. The reaction mixture was stirred at room temperature for 1hour and 2-bromo-5-chloropyrazine (Shanghai Fchemicals Technology Co.,Ltd., Shanghai, China) (250 g, 1290 mmol) was added in portion-wisemanner. The reaction mixture was stirred at room temperature for 3hours, then quenched with sat'd solution of ammonium chloride (2.0 L).The mixture was filtered through a celite pad and the filtrate wasextracted with ethyl acetate (2×2 L). The combined organic layers weredried over Na₂SO₄ and concentrated under reduced pressure. The residuewas purified via silica gel chromatography (0 to 2% ethyl acetate inhexanes) to afford 4a (215 g, 70% yield) as a viscous colorless liquid.¹H NMR (400 MHz, DMSO-d₆) δ 9.05 (d, J=1.4 Hz, 1H), 8.98 (dd, J=1.4, 0.7Hz, 1H), 4.39-4.34 (m, 2H), 1.24 (t, J=7.1 Hz, 3H).

Preparation of 2-(5-chloropyrazin-2-yl)-2,2-difluoroethanol (4b)

To a solution of 4a (215 g, 909 mmol) in ethanol (400 mL) was addedsodium borohydride (34.4 g, 909 mmol) in portion-wise manner at 0° C.The reaction mixture was stirred for 30 minutes at 0° C. Aftercompletion of reaction (monitored by TLC), the reaction mixture wasquenched with water (200 mL) and concentrated under reduced pressure togive the crude residue. The crude material was diluted with water (750mL) and extracted with ethyl acetate (2×1.0 L). The combined organicsolution was dried over Na₂SO₄ and concentrated under reduced pressure.The residue was purified by silica gel chromatography (0 to 10% ethylacetate in hexanes) to afford 4b (130 g, 73% yield) as a colorlessliquid. MS (ESI+ve ion) m/z: [M+1]=195.0. ¹H NMR (300 MHz, DMSO-d₆) δ8.97 (dt, J=1.4, 0.7 Hz, 1H), 8.82 (d, J=1.4 Hz, 1H), 5.70 (t, J=6.4 Hz,1H), 4.01 (td, J=13.8, 6.4 Hz, 2H).

Preparation of 2-chloro-5-(1,1-difluoro-2-iodoethyl)pyrazine (4c)

To a solution of 4b (130 g, 668 mmol) in acetonitrile (1.3 L) at 0° C.was added pyridine (54.0 mL, 668 mmol) followed by dropwise addition oftriflic anhydride (147 mL, 869 mmol). The reaction mixture was stirredat 0° C. for 30 minutes, and room temperature for 10 minutes. It wastreated with sodium iodide (300 g, 2004 mmol) in portion-wise manner atroom temperature. The reaction mixture was stirred at 70° C. for 2hours. It was cooled to room temperature and quenched with sat'd aqueoussodium thiosulfate solution (2.0 L) and extracted with ethyl acetate(2×2.0 L). The combined organic layers were washed with brine (2.0 L),dried over Na₂SO₄ and concentrated under reduced pressure. The residuewas purified by silica gel chromatography (0 to 2% ethyl acetate inhexanes) to afford 4c (150 g, 71% yield) as a yellow solid. ¹H NMR (300MHz, DMSO-d₆) δ 8.96 (s, 1H), 8.89 (s, 1H), 4.07 (t, J=16.4 Hz, 2H).

Preparation of (Z)-2-chloro-5-(1-fluoro-2-iodovinyl)pyrazine (4)

To a solution of 4c (150 g, 493 mmol) in DMSO (900 mL) was added 5.0 Maqueous NaOH solution (148 mL, 740 mmol). The reaction mixture wasstirred at 0° C. for 2 hours, and quenched with water (100 mL). It wasextracted with EtOAc (2×200 mL). The combined organic layers were washedwith brine (300 mL), dried over Na₂SO₄ and concentrated under reducedpressure. The residue was purified by silica gel chromatography (0 to 5%ethyl acetate in hexanes) to afford(Z)-2-chloro-5-(1-fluoro-2-iodovinyl)pyrazine (78 g, 54% yield) as awhite solid. ¹H NMR (400 MHz, Chloroform-d) δ 8.59 (q, J=1.4 Hz, 1H),8.54 (q, J=1.4 Hz, 1H), 7.05 (dd, J=34.1, 1.3 Hz, 1H).

Intermediate 5: (Z)-5-(1-fluoro-2-iodovinyl)pyrazine-2-carbonitrile

Preparation of 5-(1,1-difluoro-2-hydroxyethyl)pyrazine-2-carbonitrile(5a)

A solution of 2-(5-chloropyrazin-2-yl)-2,2-difluoroethanol (4b) (30.0 g,154 mmol) in DMF (300 mL) was degassed with nitrogen for 10 minutes. Tothe solution was sequentially added dppf (Strem Chemicals, Inc.,Newburyport, Mass., USA) (4.2 g, 7.7 mmol), Pd₂(dba)₃ (Strem Chemicals,Inc., Newburyport, Mass., USA) (7.1 g, 7.7 mmol), and Zn(CN)₂ (36.2 g,308 mmol). The reaction mixture was heated at 80° C. for 5 hours. It wascooled to room temperature and partitioned between water (200 mL) andEtOAc (200 mL). The reaction mixture was filtered through a pad ofcelite. The filtrate was transferred to a separatory funnel. The layerswere separated. The aqueous layer was extracted with ethyl acetate(2×500 mL). The combined organic solution was washed with brine (300mL), dried over Na₂SO₄ and concentrated under reduced pressure. Theresidue was purified by silica gel chromatography (0 to 20% ethylacetate in hexanes) to afford 5a (18 g, 62% yield) as a clear oil. MS(ESI+ve ion) m/z: [M+1]=no ionisation. ¹H NMR (400 MHz, DMSO-d₆) δ 9.39(d, J=1.5 Hz, 1H), 9.16 (d, J=1.5 Hz, 1H), 5.77 (t, J=6.4 Hz, 1H), 4.04(td, J=13.8, 6.4 Hz, 2H).

Preparation of 5-(1,1-difluoro-2-iodoethyl)pyrazine-2-carbonitrile (5b)

To a solution of 5-(1,1-difluoro-2-hydroxyethyl)pyrazine-2-carbonitrile(5a) (18 g, 97 mmol) in acetonitrile (180 mL) at 0° C. was addedpyridine (15.7 mL, 194 mmol) followed by dropwise addition of triflicanhydride (65.7 mL, 389 mmol). The reaction mixture was stirred at 0° C.for 30 minutes, and treated with sodium iodide (72.9 g, 486 mmol) inportion-wise manner. It was stirred at 70° C. for 3 hours. The reactionmixture was cooled to room temperature and quenched with sat'd aqueoussodium thiosulfate solution (100 mL) and extracted with ethyl acetate(2×200 mL). The combined organic solution was washed with brine (200mL), dried over Na₂SO₄ and concentrated under reduced pressure.Purification of the residue by silica gel chromatography (0 to 2% ethylacetate in hexanes) afforded 5b (10.0 g, 35% yield) as a yellow solid.MS (ESI+ve ion) m/z: [M+1]=no ionization. ¹H NMR (400 MHz, Chloroform-d)δ 9.10 (t, J=1.2 Hz, 1H), 8.98 (dd, J=1.6, 0.8 Hz, 1H), 3.91 (td,J=14.3, 1.0 Hz, 2H).

Preparation of (Z)-5-(1-fluoro-2-iodovinyl)pyrazine-2-carbonitrile (5)

To a solution of 5b (1.00 g, 3.39 mmol) in THF (10 mL) was addedpotassium tert-butoxide (0.76 g, 6.8 mmol) at −75° C. The reactionmixture was stirred at −75° C. for 30 minutes. The reaction mixture wasquenched with water (10 mL) and extracted with ethyl acetate (2×25 mL).The combined organic extracts were dried over Na₂SO₄ and concentratedunder reduced pressure. Purification of the residue by silica gelchromatography (0 to 5% ethyl acetate in hexanes) afforded(Z)-5-(1-fluoro-2-iodovinyl)pyrazine-2-carbonitrile (5) (0.34 g, 36%yield) as an off-white solid. MS (ESI+ve ion) m/z: [M+1]=no ionization.¹H NMR (400 MHz, Chloroform-d) δ 8.92 (t, J=1.4 Hz, 1H), 8.84 (t, J=1.2Hz, 1H), 7.38 (d, J=33.5 Hz, 1H).

Intermediate 6:(4R,5R)-4-(5-bromo-2-fluorophenyl)-4-methyl-5-(2,2,2-trifluoroethoxy)-5,6-dihydro-4H-1,3-oxazin-2-amine

Preparation of(R,E)-N-(1-(5-bromo-2-fluorophenyl)ethylidene)-2-methylpropane-2-sulfinamide(6a)

To a solution of 1-(5-bromo-2-fluorophenyl)ethanone (2.5 kg, 11.5 mol)in THF (25.0 L) was added (R)-2-methylpropane-2-sulfinamide (2.1 kg,17.3 mol) and titanium(IV) ethoxide (7.9 L, 34.6 mol) at roomtemperature under nitrogen atmosphere. The reaction mixture was refluxedat 65° C. for 12 hours. It was quenched with brine (5.0 L) and dilutedwith ethyl acetate (5.0 L). The mixture was stirred for 30 minutes. Thethick suspension was filtered through a bed of celite and the filteredcake was washed with ethyl acetate (3×2 L). The filtrate was dried overNa₂SO₄ and concentrated under reduced pressure to give crude residuewhich was purified on a silica gel column (0 to 15% ethyl acetate inhexanes) to afford 6a (3.0 kg, 88% yield) as a light yellow solid. MS(ESI+ve ion) m/z: [M+1]=320/322. ¹H NMR (400 MHz, Chloroform-d) δ 7.78(dd, J=6.6, 2.6 Hz, 1H), 7.54 (ddd, J=8.9, 4.3, 2.5 Hz, 1H), 7.03 (dd,J=10.6, 8.7 Hz, 1H), 2.77 (d, J=3.6 Hz, 3H), 1.33 (s, 9H).

Preparation of methyl 2-(2,2,2-trifluoroethoxy)acetate (6b)

To a solution of trifluoroethanol (Avra Synthesis Private Ltd,Hyderabad, India) (150 g, 1.5 mol) in THF (2500 mL) at 0° C. was addedsodium hydride (36 g, 1.5 mol) in small portions. The reaction mixturewas stirred for 60 minutes at 0° C. and methyl 2-bromoacetate (206 g,1.3 mol) was added. The reaction mixture was stirred for 60 minutes atroom temperature and quenched with cold water (100 mL). It was extractedwith ethyl acetate (2×2000 mL). The combined organic solution wasconcentrated under reduced pressure. The crude product was purified bydistillation at 120° C. under 560 mm/Hg to provide 6b (120 g, 54%yield). ¹H NMR (300 MHz, Chloroform-d) δ 4.24 (s, 2H), 4.05-3.92 (m,2H), 3.77 (s, 3H).

Preparation of(3R)-methyl-3-(5-bromo-2-fluorophenyl)-3-((R)-1,1-dimethylethylsulfinamido)-2-(2,2,2-trifluoroethoxy)butanoate (6c)

To a solution of 6b (129 g, 749 mmol) in THF (2500 mL) was added LDA(2.0 M in THF, 375 mL) at −78° C. over a period of 2 hours and thereaction mixture was stirred for 60 minutes at −78° C.(R,E)-N-(1-(5-bromo-2-fluorophenyl)ethylidene)-2-methylpropane-2-sulfinamide(6a) (60.0 g, 187 mmol) in THF (300 mL) was added at −78° C. and thereaction mixture was stirred for 1 hours at −30° C. It was quenched withsat'd aqueous ammonium chloride solution (2000 mL) and extracted withethyl acetate (3×2000 mL). The combined organic solution was driedNa₂SO₄ and concentrated under reduced pressure. The crude product waspurified by flash column chromatography (50% of ethyl acetate inhexanes) to give 6c (50 g, 54% yield). MS (ESI, positive ion) m/z:492.0/494.0 (M+1). ¹H NMR (400 MHz, Chloroform-d) δ 7.56 (dt, J=7.2, 2.2Hz, 1H), 7.45 (m, 1H), 7.02-6.90 (m, 1H), 4.99-4.91 (m, 1H), 4.12 (td,J=7.1, 1.7 Hz, 1H), 4.02-3.89 (m, 2H), 3.78 (d, J=1.8 Hz, 3H), 3.68 (m,1H), 1.90-1.83 (m, 2H), 1.28-1.20 (m, 9H).

Preparation of(R)—N-((2R)-2-(5-bromo-2-fluorophenyl)-4-hydroxy-3-(2,2,2-trifluoroethoxy)butan-2-yl)-2-methylpropane-2-sulfinamide(6d)

To a solution of 6c (50 g, 102 mmol) in THF (1000 mL) was added LiBH₄(Sainor Laboratories Private Ltd., Hyderabad, India) (2.0 M in THF, 76mL) at 0° C. and the reaction mixture was stirred for 12 hours at roomtemperature. The reaction mixture was quenched by the addition of amixture of acetic acid (50 mL) and water (1000 mL), and then extractedwith ethyl acetate (3×1000 mL). The combined organic solution was driedover Na₂SO₄ and concentrated under reduced pressure. The residue waspurified by flash column chromatography (70% of ethyl acetate inhexanes) to afford 6d (35 g, 74% yield) as a single diastereomer.Relative stereochemistry confirmed by NMR analysis of 6. MS (ESI,positive ion) m/z: 464.0/466.0 (M+1). ¹H NMR (400 MHz, Chloroform-d) δ7.57 (dd, J=7.2, 2.5 Hz, 1H), 7.43 (m, 1H), 6.97 (dd, J=12.4, 8.7 Hz,1H), 5.15 (d, J=3.1 Hz, 1H), 4.03-3.91 (m, 3H), 3.85-3.75 (m, 1H),3.71-3.60 (m, 2H), 1.89 (s, 3H), 1.22 (s, 9H).

Preparation of(3R)-3-amino-3-(5-bromo-2-fluorophenyl)-2-(2,2,2-trifluoroethoxy)butan-1-ol(6e)

To a solution of 6d (35 g, 75 mmol) in methanol (500 mL) was added 4.0 MHCl solution in dioxane (150 mL) at 0° C. and the reaction mixture wasstirred for 4 hours at room temperature. The reaction mixture wasconcentrated under reduced pressure and the residue was partitionedbetween water (1000 mL) and ethyl acetate (1000 mL). The layers wereseparated, the organic layer was discarded. The aqueous layer wasbasified with sat'd aqueous sodium bicarbonate to pH˜9.0, and extractedwith ethyl acetate (2×1000 mL). The combined organic solution was driedover Na₂SO₄ and concentrated under reduced pressure. Purification of thecrude material via flash column chromatography (10% methanol in DCM)afforded 6e (25 g, 92% yield) as a single diastereomer. Relativestereochemistry confirmed by NMR analysis of 6. MS (ESI, positive ion)m/z: 360.0/362.0 (M+1). ¹H NMR (300 MHz, DMSO-d₆) δ 7.80 (dd, J=7.1, 2.5Hz, 1H), 7.66 (m, 1H), 7.29 (m, 1H), 4.33 (m, 2H), 4.02 (t, J=3.8 Hz,1H), 3.60 (dd, J=12.3, 3.0 Hz, 1H), 3.40-3.24 (m, 2H), 1.72 (s, 3H).Note: NH₂ proton not observed.

Preparation oftert-butyl-((4R)-4-(5-bromo-2-fluorophenyl)-4-methyl-5-(2,2,2-trifluoroethoxy)-5,6-dihydro-4H-1,3-oxazin-2-yl)carbamate (6f)

A solution of 6e (25.0 g, 69.4 mmol) and cyanogen bromide (36.8 g, 347mmol) in ethanol (250 mL) in a sealed tube was heated at 80° C. for 3days. The reaction mixture was concentrated under reduced pressure. Theresidue was partitioned between ethyl acetate (1000 mL) and sat'daqueous sodium bicarbonate solution (250 mL). The layers were separated,and the aqueous layer was discarded. The organic layer was washed withsat'd aqueous sodium bicarbonate solution (2×250 mL), dried over Na₂SO₄,and concentrated under reduced pressure. The residue was purified byflash column chromatography (80% ethyl acetate in hexanes) to give apartially pure product. The partially pure product was dissolved in THF(250 mL), treated with triethyl amine (11.9 mL, 139 mmol) followed byBoc-anhydride (22.7 g, 104 mmol). The reaction mixture was stirred for 4hours at room temperature. The mixture was diluted with ethyl acetate(500 mL) and washed with water (2×200 mL). The organic layer wasconcentrated under reduced pressure. The residue was purified by flashcolumn chromatography (20% ethyl acetate in hexanes) to provide 6f (15g, 44% yield) as a single diastereomer. Relative stereochemistryconfirmed by NMR analysis of 6. MS (ESI, positive ion) m/z: 485.0/487.0(M+1). ¹H NMR (400 MHz, Chloroform-d) δ 9.95 (s, 1H), 7.48 (m, 2H), 7.00(dd, J=11.4, 8.5 Hz, 1H), 4.36-4.24 (m, 2H), 4.12 (dt, J=14.9, 7.6 Hz,2H), 4.03-3.94 (m, 1H), 3.93-3.86 (m, 1H), 1.78 (s, 3H), 1.53 (s, 9H).

Preparation of(4R)-4-(5-bromo-2-fluorophenyl)-4-methyl-5-(2,2,2-trifluoroethoxy)-5,6-dihydro-4H-1,3-oxazin-2-amine(6)

To a solution of 6f (15.0 g, 30.9 mmol) in DCM (150 mL) was added TFA(20 mL) at 0° C. and the resulting solution was stirred for 12 hours atroom temperature. It was concentrated under reduced pressure. Theresidue was diluted with ethyl acetate (500 mL) and washed with 20%sodium bicarbonate solution (3×150 mL). The organic layer was dried andconcentrated under reduced pressure. The crude product was purified byflash column chromatography (10% methanol in DCM) to provideIntermediate 6 (9.5 g, 80% yield). MS (ESI, positive ion) m/z:385.0/387.0 (M+1). ¹H NMR (400 MHz, DMSO-d₆) δ 7.53 (dd, J=7.1, 4.6 Hz,2H), 7.27-7.07 (m, 1H), 5.91 (s, 3H), 4.27 (q, J=9.3 Hz, 2H), 4.17-4.07(m, 1H), 3.56 (d, J=12.1 Hz, 1H), 1.44 (d, J=1.5 Hz, 3H). The relativestereochemistry of 6 was confirmed by 2-D NMR analysis.

Intermediate 7: tert-butyl((2R,5R)-5-(5-bromo-2-fluorophenyl)-2,5-dimethyl-2-(trifluoromethyl)-5,6-dihydro-2H-1,4-oxazin-3-yl)carbamate

To a solution of(3R,6R)-3-(5-bromo-2-fluoro-phenyl)-3,6-dimethyl-6-(trifluoromethyl)-2H-1,4-oxazin-5-amine(7a, prepared according to the procedures reported in WO 2012095463 A1)(12.20 g, 33.05 mmol) in DCM (120.00 mL) was added Boc₂O (8.66 g, 39.7mmol) and TEA (4.01 g, 39.6 mmol). The mixture was stirred at 25° C. for20 minutes, then partitioned between DCM (200 mL) and water (50 mL). Theorganic phase was separated, washed with brine (2×30 mL), dried overNa₂SO₄, filtered and concentrated under reduced pressure. The residuewas purified by silica gel chromatography (petroleum ether/ethylacetate=50/1 to 8:1) to afford the title compound (10.11 g, 63% yield)as a white solid. MS (ESI+ve ion) m/z: [M+1]=469.1/471.1. ¹H NMR (400MHz, Chloroform-d) δ 11.00 (br, 1H), 7.47-7.43 (m, 1H), 7.42-7.41 (m,1H), 7.06-7.00 (m, 1H), 4.41-4.05 (dd, 2H), 1.68 (s, 3H), 1.60 (s, 9H),1.56 (s, 3H).

Intermediate 8:2-(((3,5-bis(trifluoromethyl)phenyl)sulfonyl)fluoromethyl)-5-chloropyridine

Preparation of2-(((3,5-bis(trifluoromethyl)phenyl)thio)methyl)-5-chloropyridine (8a)

Sodium hydroxide (5.4 mL of 2 N solution, 10.8 mmol) was added dropwiseto a solution of 3,5-bis-trifluoromethyl benzenethiol (Sigma-AldrichChemical Company, Inc., St. Louis, Mo., USA) (1.8 mL, 11 mmol) in MeOH(3 mL) at room temperature. This mixture was stirred for 5 minutes andthen 5-chloro-2-(chloromethyl)pyridine (Sigma-Aldrich Chemical Company,Inc., St. Louis, Mo., USA) (1.8 g, 11 mmol) was added as a solution inMeOH (10 mL). This mixture was stirred for 2 hours at room temperatureand then it was concentrated to about half volume in vacuo. EtOAc andhalf saturated aqueous ammonium chloride were added, the layers wereseparated, and the aqueous layer was extracted with EtOAc. The combinedorganic layers were dried over anhydrous MgSO₄, filtered, andconcentrated in vacuo to give2-(((3,5-bis(trifluoromethyl)phenyl)thio)methyl)-5-chloropyridine (8a)(4.1 g, 101% yield) as a solid. MS m/z=372 [M+H]⁺. ¹H NMR (400 MHz,CDCl₃) δ ppm 8.49 (d, J=2.35 Hz, 1H) 7.75 (s, 2H) 7.61-7.65 (m, 2H) 7.32(d, J=8.08 Hz, 1H) 4.32 (s, 2H).

Preparation of2-(((3,5-bis(trifluoromethyl)phenyl)sulfonyl)methyl)-5-chloropyridine(8b)

mCPBA (Sigma-Aldrich Chemical Company, Inc., St. Louis, Mo., USA) (6.2g, 28 mmol) was added to a solution of2-(((3,5-bis(trifluoromethyl)phenyl)thio)methyl)-5-chloropyridine (8a)(4.1 g, 11 mmol) in DCM (40 mL) and the mixture was stirred for 2 hours.Saturated aqueous sodium bicarbonate solution and DCM were added and thebiphasic mixture was stirred vigorously until all solids were dissolved.The layers were separated and the organic layer was washed withsaturated aqueous sodium bicarbonate solution, dried over anhydrousMgSO₄, filtered, and concentrated in vacuo to give a mixture of2-(((3,5-bis(trifluoromethyl)phenyl)sulfonyl)methyl)-5-chloropyridine(8b) and2-(((3,5-bis(trifluoromethyl)phenyl)sulfonyl)methyl)-5-chloropyridine-N-oxideas a white solid, that was taken directly to the next step withoutfurther purification.

Iron powder (1.55 g, 27.9 mmol) and glacial acetic acid (5.4 mL, 93mmol) were added to a suspension of2-(((3,5-bis(trifluoromethyl)phenyl)sulfonyl)methyl)-5-chloropyridine(8b) and2-(((3,5-bis(trifluoromethyl)phenyl)sulfonyl)methyl)-5-chloropyridine-N-oxidein EtOH (50 mL). This mixture was heated to 75° C. and then the iron wasremoved by filtering through a pad of celite while still hot. Thefiltrate was concentrated in vacuo and then suspended in 1:1EtOAc/heptane (15 mL). After cooling to 0° C. for 1 hour, the suspensionwas filtered and the collected solid was air dried to give2-(((3,5-bis(trifluoromethyl)phenyl)sulfonyl)methyl)-5-chloropyridine(8b) (2.9 g, 78% yield for 2 steps) as a white solid. MS m/z=404 [M+H]⁺.¹H NMR (400 MHz, CDCl₃) δ ppm 8.31 (d, J=2.35 Hz, 1H) 8.12 (s, 1H) 8.05(s, 2H) 7.76 (d, J=8.02 Hz, 1H) 7.50 (d, J=8.41 Hz, 1H) 4.58 (s, 2H).

Preparation of2-(((3,5-bis(trifluoromethyl)phenyl)sulfonyl)fluoromethyl)-5-chloropyridine(8)

LDA (Sigma-Aldrich Chemical Company, Inc., St. Louis, Mo., USA) (2.0 Msolution in THF/heptane/ethylbenzene, 3.78 mL) was added dropwise to asolution of2-(((3,5-bis(trifluoromethyl)phenyl)sulfonyl)-methyl)-5-chloropyridine(8b) (2.91 g, 7.21 mmol) in THF (25 mL) at −78° C. This mixture wasstirred for 15 minutes before NFSI (Sigma-Aldrich Chemical Company,Inc., St. Louis, Mo., USA) (2.39 g, 7.57 mmol) was added as a solid.This mixture was stirred at −78° C. for 30 minutes, then at roomtemperature for 30 minutes. The resulting suspension was partitionedbetween water and EtOAc. The layers were separated and the organic layerwas dried over anhydrous MgSO₄, filtered, and concentrated in vacuo togive a solid. The solid was fused to silica gel and the product waspurified by silica gel chromatography (0 to 20% EtOAc/heptane) to give2-(((3,5-bis(trifluoromethyl)phenyl)sulfonyl)fluoromethyl)-5-chloropyridine(8) (2.3 g, 76% yield) as a white solid. MS m/z=422 [M+H]⁺. ¹H NMR (400MHz, CDCl₃) δ ppm 8.60-8.66 (m, 1H) 8.34 (s, 2H) 8.23 (s, 1H) 7.84 (d,J=8.30 Hz, 1H) 7.56 (d, J=8.22 Hz, 1H) 6.24 (d, J=45.97 Hz, 1H).

Intermediate 9:(Z)-6-(1-fluoro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)vinyl)nicotinonitrile

A mixture of (Z)-6-(1-fluoro-2-iodovinyl)nicotinonitrile (3) (1.00 g,3.65 mmol), KOAc (0.71 g, 7.30 mmol) and bis(pinacolato)diboron (1.39 g,5.47 mmol) in 1,4-dioxane (20 mL) was purged with nitrogen for 10minutes then treated with PdCl₂(dppf)-CH₂Cl₂ adduct (0.15 g, 0.18 mmol).The mixture was purged with nitrogen for 10 minutes then heated at 90°C. for 16 hours. After cooling to room temperature, the reaction mixturewas filtered through a celite pad and washed with ethyl acetate (20 mL).The filtrate was evaporated under reduced pressure. The residue waspurified by silica gel chromatography (20% to 30% EtOAc in hexane) toprovide(Z)-6-(1-fluoro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)vinyl)nicotinonitrile(9) (0.50 g, 1.82 mmol, 50% yield) as an off-white solid. MS (ESIpositive ion) m/z: not ionized. ¹H NMR (300 MHz, Chloroform-d) δ8.99-8.63 (m, 1H), 8.20-7.84 (m, 1H), 7.73 (d, J=8.2 Hz, 1H), 6.26 (d,J=52.8 Hz, 1H), 1.37-1.27 (m, 12H). ¹⁹F NMR (376 MHz, Chloroform-d) δ−112.82 (s).

Intermediate 10: tert-butyl ((2R,5R)-5-(6-bromo-3-fluoropyridin-2-yl)-2,5-dimethyl-2-(trifluoromethyl)-5,6-dihydro-2H-1,4-oxazin-3-yl)carbamate

At 0° C., a solution of(2R,5R)-5-(6-bromo-3-fluoropyridin-2-yl)-2,5-dimethyl-2-(trifluoromethyl)-5,6-dihydro-2H-1,4-oxazin-3-amine(10a, prepared according to the procedures reported in WO 2012095469 A1)(280 mg, 0.75 mmol) in DCM (10 mL) was treated withdi-isopropylethylamine (0.53 mL, 3.03 mmol) followed by Boc-anhydride(0.44 mL, 1.89 mmol). After the reaction mixture was stirred at roomtemperature for 16 hours, it was partitioned between DCM (50 mL) andwater (50 mL). Organic layer was dried over Na₂SO₄ and concentratedunder reduced pressure. The crude residue was purified by silica gelchromatography (0% to 10% ethyl acetate in hexanes) to provide compound10 (280 mg, 79% yield) as an off-white solid. MS (ESI positive ion) m/z:471.2 (M+H). ¹H NMR (400 MHz, Chloroform-d) δ 11.25 (br. s, 1H), 7.48(dd, J=8.4, 3.1 Hz, 1H), 7.35 (dd, J=10.3, 8.4 Hz, 1H), 4.26 (q, J=12.1Hz, 2H), 1.63-1.49 (m, 15H).

EXAMPLES Example 100(1R,5S,6R)-5-(5-((Z)-2-(5-bromopyridin-2-yl)-2-fluorovinyl)-2-fluorophenyl)-5-(difluoromethyl)-2-oxa-4-azabicyclo[4.1.0]hept-3-en-3-amine

Preparation ofN-((1R,5S,6R)-5-(5-bromo-2-fluorophenyl)-5-(difluoromethyl)-2-oxa-4-azabicyclo[4.1.0]hept-3-en-3-yl)benzamide(100b)

Triethylamine (1.00 mL, 7.16 mmol) was added to a solution of benzoicanhydride (1.24 mL, 6.56 mmol) and(1R,5S,6R)-5-(5-bromo-2-fluorophenyl)-5-(difluoromethyl)-2-oxa-4-azabicyclo[4.1.0]hept-3-en-3-amine(100a, prepared according to the procedures reported in WO 2014138484A1) (2.0 g, 6.0 mmol) in DMF (12 mL). The mixture was stirred for 4hours at room temperature; then water (50 mL) was added slowly. Theresulting suspension was stirred for 30 minutes, filtered, and thecollected solid was washed with water several times and air dried togive 100b (2.61 g, 99% yield) as a white solid. MS m/z=439.0/441.0[M+H]⁺.

Preparation ofN-((1R,5S,6R)-5-(difluoromethyl)-5-(2-fluoro-5-vinylphenyl)-2-oxa-4-azabicyclo[4.1.0]hept-3-en-3-yl)benzamide(100c)

A mixture ofN-((1R,5S,6R)-5-(5-bromo-2-fluorophenyl)-5-(difluoromethyl)-2-oxa-4-azabicyclo[4.1.0]hept-3-en-3-yl)benzamide(100b) (2.60 g, 5.92 mmol), potassium vinyltrifluoroborate (0.99 g, 7.4mmol), methylaminophenyllpalladium(II) chloride (0.21 g, 0.30 mmol), andpotassium acetate (1.74 mg, 17.8 mmol) was dissolved in 3:1 CH₃CN/water(20 mL) and sparged with argon for 5 minutes. The mixture was heated to75° C. for 4 hours, and then cooled to room temperature. EtOAc and waterwere added, the layers were separated, and the organic layer was driedover magnesium sulfate, filtered, and concentrated in vacuo to give anoil. The oil was purified by silica gel chromatography (20%EtOAc/heptane) to giveN-((1R,5S,6R)-5-(difluoromethyl)-5-(2-fluoro-5-vinylphenyl)-2-oxa-4-azabicyclo[4.1.0]hept-3-en-3-yl)benzamide(100c) (1.08 g, 47% yield) as a solid. MS m/z=387.0 [M+1-1]+. ¹H NMR(400 MHz, CDCl₃) δ ppm 8.23-8.28 (m, 2H) 7.44 (s, 4H) 7.34 (dd, J=7.63,1.96 Hz, 1H) 7.08-7.19 (m, 1H) 6.54-6.66 (m, 1H) 6.39 (t, J=54.60 Hz,1H) 5.60 (d, J=17.41 Hz, 1H) 5.20 (d, J=10.96 Hz, 1H) 4.21 (td, J=6.94,2.93 Hz, 1H) 2.13 (dt, J=9.34, 7.07 Hz, 1H) 1.68-1.77 (m, 1H) 1.16-1.27(m, 1H). NH peak was not observed. ¹⁹F NMR (376 MHz, CDCl₃) δ −113.38(s, 1F), −126.49 (s, 2F).

Preparation ofN-((1R,5S,6R)-5-(difluoromethyl)-5-(2-fluoro-5-formylphenyl)-2-oxa-4-azabicyclo[4.1.0]hept-3-en-3-yl)benzamide(100d)

Osmium tetroxide (2.5 wt. % solution in 2-methyl-2-propanol, 0.27 mL,0.028 mmol) was added to a mixture ofN-((1R,5S,6R)-5-(difluoromethyl)-5-(2-fluoro-5-vinylphenyl)-2-oxa-4-azabicyclo[4.1.0]hept-3-en-3-yl)benzamide(100c) (1.08 g, 2.80 mmol) and 4-methylmorpholine-4-oxide (0.66 g, 5.59mmol) in THF (9 mL) and water (6 mL) at room temperature. The mixturewas stirred for 4 hours, then sodium (meta)periodate (1.79 g, 8.39 mmol)was added. The resulting suspension was stirred for 1 hour, thenpartitioned between EtOAc and saturated aqueous sodium thiosulfatesolution. The layers were separated and the organic layer was washedwith saturated aqueous sodium thiosulfate followed by brine, dried overmagnesium sulfate, and concentrated in vacuo to give an oil. The oil waspurified by silica gel chromatography (30 to 100% EtOAc/heptane) to giveN-((1R,5S,6R)-5-(difluoromethyl)-5-(2-fluoro-5-formylphenyl)-2-oxa-4-azabicyclo[4.1.0]hept-3-en-3-yl)benzamide(100d) (1.03 g, 95% yield) as a white solid. MS m/z=389.0 [M+H]⁺. ¹H NMR(400 MHz, CDCl₃) δ ppm 12.20 (br. s., 1H) 9.92 (s, 1H) 8.24 (br. s., 2H)8.01 (td, J=5.38, 2.54 Hz, 1H) 7.93 (br. s., 1H) 7.49-7.57 (m, 1H)7.32-7.47 (m, 3H) 6.37 (t, J=55.16 Hz, 1H) 4.28 (td, J=6.75, 2.93 Hz,1H) 2.10-2.20 (m, 1H) 1.74 (br. s., 1H) 1.22-1.32 (m, 1H). ¹⁹F NMR (376MHz, CDCl₃) δ −101.97 (s, 1F), −126.31 (s, 2F).

Preparation ofN-((1R,5S,6R)-5-(5-((Z)-2-(5-bromopyridin-2-yl)-2-fluorovinyl)-2-fluorophenyl)-5-(difluoromethyl)-2-oxa-4-azabicyclo[4.1.0]hept-3-en-3-yl)benzamide(100e)

Lithium bis(trimethylsilyl)amide solution (1.0 M in THF, 1.60 mL) wasadded to a solution ofN-((1R,5S,6R)-5-(difluoromethyl)-5-(2-fluoro-5-formylphenyl)-2-oxa-4-azabicyclo[4.1.0]hept-3-en-3-yl)benzamide(100d) (283 mg, 0.73 mmol) and2-(((3,5-bis(trifluoromethyl)phenyl)sulfonyl)fluoromethyl)-5-bromopyridine(1) (442 mg, 0.95 mmol) in THF (3 mL) at room temperature. The mixturewas stirred for 5 minutes, then DMSO (3 mL) was added. This mixture wasstirred for 30 minutes. EtOAc and saturated aqueous ammonium chloridesolution were then added. The layers were separated and the organiclayer was washed with water (2×), dried over magnesium sulfate,filtered, and concentrated in vacuo to give an oil that was purified bysilica gel chromatography (20% EtOAc/heptane) to give 100e (0.29 g, 71%yield, 7:3 mixture of olefin isomers) as a white solid. MS m/z=560.0[M+H]⁺.

Preparation of(1R,5S,6R)-5-(5-((Z)-2-(5-bromopyridin-2-yl)-2-fluorovinyl)-2-fluorophenyl)-5-(difluoromethyl)-2-oxa-4-azabicyclo[4.1.0]hept-3-en-3-amine(100)

A mixture ofN-((1R,5S,6R)-5-(5-((Z)-2-(5-bromopyridin-2-yl)-2-fluorovinyl)-2-fluorophenyl)-5-(difluoromethyl)-2-oxa-4-azabicyclo[4.1.0]hept-3-en-3-yl)benzamide(0.29 g, 7:3 mixture of olefin isomers, 0.51 mmol) and1,8-diazabicyclo-[5.4.0]undec-7-ene (0.23 mL, 1.54 mmol) in MeOH (2.5mL) was heated to 60° C. for 4 hours, then cooled to room temperature.The mixture was concentrated in vacuo and the resulting oil was purifiedby silica gel chromatography (0 to 50% EtOAc/DCM) to give(1R,5S,6R)-5-(5-((Z)-2-(5-bromopyridin-2-yl)-2-fluorovinyl)-2-fluorophenyl)-5-(difluoromethyl)-2-oxa-4-azabicyclo[4.1.0]hept-3-en-3-amine(100) (122 mg, 52% yield) as a yellow solid. MS m/z=456.0 [M+H]⁺. ¹H NMR(400 MHz, CDCl₃) δ ppm 8.56-8.61 (m, 1H), 7.79-7.87 (m, 2H), 7.55-7.63(m, 1H), 7.36 (dd, J=8.41, 1.17 Hz, 1H), 7.06 (dd, J=11.93, 8.41 Hz,1H), 6.94 (d, J=38.73 Hz, 1H), 6.23 (t, J=55.20 Hz, 1H), 4.78 (br. s.,2H), 3.86-3.93 (m, 1H), 1.78-1.87 (m, 1H), 1.39-1.47 (m, 1H), 0.89-0.99(m, 1H).

Example 101(1R,5S,6R)-5-(5-((Z)-2-(5-chloropyridin-2-yl)-2-fluorovinyl)-2-fluorophenyl)-5-(difluoromethyl)-2-oxa-4-azabicyclo[4.1.0]hept-3-en-3-amine

This compound (29 mg, 0.07 mmol, 32% yield for 2 steps) as a white solidwas prepared in a fashion similar to that described for Example 100,here starting with2-(((3,5-bis(trifluoromethyl)phenyl)sulfonyl)fluoromethyl)-5-chloropyridine(8) (120 mg, 0.29 mmol) and aldehyde 100d (85 mg, 0.22 mmol). MSm/z=412.0 [M+H]⁺. ¹H NMR (400 MHz, Chloroform-d) δ ppm 8.50 (d, J=2.35Hz, 1H), 7.84 (dd, J=7.73, 2.05 Hz, 1H), 7.69 (dd, J=8.41, 2.35 Hz, 1H),7.57-7.64 (m, 1H), 7.44 (dd, J=8.41, 1.17 Hz, 1H), 7.07 (dd, J=11.93,8.61 Hz, 1H), 6.95 (d, J=38.93 Hz, 1H), 6.21 (t, J=56.70 Hz, 1H), 4.67(s, 2H), 3.91 (t, J=5.48 Hz, 1H), 1.77-1.88 (m, 1H), 1.43 (br. s., 1H),0.89-0.99 (m, 1H).

Example 1026-((Z)-2-(3-((1R,5S,6R)-3-amino-5-(difluoromethyl)-2-oxa-4-azabicyclo[4.1.0]hept-3-en-5-yl)-4-fluorophenyl)-1-fluorovinyl)nicotinonitrile

Tris(dibenzylideneacetone)dipalladium (0) (8.0 mg, 8.2 μmol) and S-Phos(7.0 mg, 16 μmol) were mixed in DMA (0.25 mL) and then argon was bubbledthrough the solution for 5 minutes at 50° C. This solution was added toa solution of zinc cyanide (14 mg, 0.12 mmol) and(1R,5S,6R)-5-(5-((Z)-2-(5-bromopyridin-2-yl)-2-fluorovinyl)-2-fluorophenyl)-5-(difluoromethyl)-2-oxa-4-azabicyclo[4.1.0]hept-3-en-3-amine(100) (75 mg, 0.16 mmol) in DMA (0.5 mL) under argon, and then thismixture was heated to 110° C. for 16 hours. The reaction was cooled toroom temperature, diluted with EtOAc, washed with saturated aqueoussodium bicarbonate (2×). The organic solution was dried over magnesiumsulfate, filtered and concentrated in vacuo to give a solid. The solidwas suspended in 1:1 DCM/heptane and cooled to 0° C. for 2 hours, thenfiltered to give6-((Z)-2-(3-((1R,5S,6R)-3-amino-5-(difluoromethyl)-2-oxa-4-azabicyclo[4.1.0]hept-3-en-5-yl)-4-fluorophenyl)-1-fluorovinyl)nicotinonitrile(102) (33 mg, 50% yield) as an off-white solid. MS m/z=403.0 [M+H]⁺. ¹HNMR (400 MHz, DMSO-d₆) δ ppm 9.10 (d, J=1.96 Hz, 1H) 8.46 (dd, J=8.51,2.15 Hz, 1H) 7.97 (dd, J=7.73, 2.05 Hz, 1H) 7.78-7.89 (m, 2H) 7.25-7.39(m, 2H) 6.20 (t, J=55.90 Hz, 1H) 6.00 (s, 2H) 4.00-4.06 (m, 1H)1.76-1.83 (m, 1H) 1.16-1.28 (m, 1H) 0.92 (dt, J=9.39, 6.55 Hz, 1H).

Example 103(2R,5R)-5-(5-((Z)-2-(5-chloropyridin-2-yl)-2-fluorovinyl)-2-fluorophenyl)-2,5-dimethyl-2-(trifluoromethyl)-5,6-dihydro-2H-1,4-oxazin-3-amine

Preparation of tert-butyl((2R,5R)-5-(2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2,5-dimethyl-2-(trifluoromethyl)-5,6-dihydro-2H-1,4-oxazin-3-yl)carbamate(103a)

A mixture of tert-butyl((2R,5R)-5-(5-bromo-2-fluorophenyl)-2,5-dimethyl-2-(trifluoromethyl)-5,6-dihydro-2H-1,4-oxazin-3-yl)carbamate(7) (0.100 g, 0.213 mmol), bis(pinacolato)diboron (Sigma-Aldrich, St.Louis, Mo., USA, 0.108 g, 0.426 mmol), potassium acetate (Sigma-Aldrich,St. Louis, Mo., USA, 74 mg, 0.75 mmol), and1,1′-bis(diphenylphosphino)ferrocene palladium(II) dichloridedichloromethane adduct (Strem Chemicals, Inc., Newburyport, Mass., USA,0.035 g, 0.043 mmol) in1,4-dioxane (3 mL) was heated at 90° C. for 3hours. The reaction mixture was then cooled to 23° C., diluted withEtOAc/Heptane (1:1, 20 mL), and the solid was removed by filtration. Thefiltrate was concentrated and purified twice by silica gelchromatography (0 to 40% EtOAc in heptane then 0 to 30% EtOAc inheptane) to afford 103a (0.042 g, 0.081 mmol, 38% yield). ¹H NMR (400MHz, Chloroform-d) δ ppm 7.75-7.83 (m, 1H) 7.72 (d, J=8.61 Hz, 1H) 7.11(dd, J=12.42, 7.92 Hz, 1H) 4.34 (d, J=12.32 Hz, 1H) 4.09 (d, J=4.89 Hz,1H) 1.75 (s, 3H) 1.70 (br s, 3H) 1.56 (s, 9H) 1.33 (s, 12H). NH peak wasnot observed.

Preparation of(2R,5R)-5-(5-((Z)-2-(5-chloropyridin-2-yl)-2-fluorovinyl)-2-fluorophenyl)-2,5-dimethyl-2-(trifluoromethyl)-5,6-dihydro-2H-1,4-oxazin-3-amine(103)

tert-Butyl((2R,5R)-5-(2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2,5-dimethyl-2-(trifluoromethyl)-5,6-dihydro-2H-1,4-oxazin-3-yl)carbamate(103a) (0.042 g, 0.081 mmol),(Z)-5-chloro-2-(1-fluoro-2-iodovinyl)pyridine (7) (0.025 g, 0.089 mmol),1,1-bis[(di-tert-butyl-p-methylaminophenyl]palladium(II) chloride(Sigma-Aldrich, St. Louis, Mo., USA, 5.8 mg, 8.1 μmol) and potassiumphosphate (Sigma-Aldrich, St. Louis, Mo., USA, 0.028 g, 0.20 mmol) werecombined in a vial, which was capped and then evacuated and backfilledwith N₂ (×3). Dioxane (0.5 mL) and water (0.1 mL) were added and themixture heated to 80° C. for 18 hours. The mixture was then diluted withwater and extracted with EtOAc. The organic solution was dried overMgSO₄, and concentrated in vacuo. The residue was purified by silica gelchromatography (5 to 60% (3:1 EtOAc/EtOH) in heptane) to provide((2R,5R)-5-(5-((Z)-2-(5-chloropyridin-2-yl)-2-fluorovinyl)-2-fluorophenyl)-2,5-dimethyl-2-(trifluoromethyl)-5,6-dihydro-2H-1,4-oxazin-3-amine(103) (0.006 g, 17% yield) as an off-white oil. MS (ESI+) m/z:[M+1]=446.1. ¹H NMR (400 MHz, Chloroform-d) δ ppm 8.54 (d, J=2.15 Hz,1H) 7.69-7.79 (m, 2H) 7.62-7.71 (m, 1H) 7.52-7.59 (m, 1H) 6.95-7.11 (m,2H) 4.08-4.14 (m, 1H) 3.95 (d, J=11.74 Hz, 1H) 1.96-2.26 (m, 2H) 1.58(s, 3H) 1.49 (s, 3H). ¹⁹F NMR (376 MHz, Chloroform-d) δ ppm−80.13-−72.46 (m, 3F) −111.65 (d, J=1.79 Hz, 1F) −124.11 (s, 1F).

Example 1046-((Z)-2-(3-((3R,6R)-5-amino-3,6-dimethyl-6-(trifluoromethyl)-3,6-dihydro-2H-1,4-oxazin-3-yl)-4-fluorophenyl)-1-fluorovinyl)nicotinonitrile

Preparation of tert-butyl((2R,5R)-5-(5-bromo-2-fluorophenyl)-2,5-dimethyl-2-(trifluoromethyl)-5,6-dihydro-2H-1,4-oxazin-3-yl)((2-(trimethylsilyl)ethoxy)methyl)carbamate(104a)

To a heat-gun dried 50 mL round bottom flask charged with a stir bar wasadded sodium hydride (51 mg, 60 wt. % in mineral oil, 1.3 mmol) under anitrogen atmosphere. tert-Butyl((2R,5R)-5-(5-bromo-2-fluorophenyl)-2,5-dimethyl-2-(trifluoromethyl)-5,6-dihydro-2H-1,4-oxazin-3-yl)carbamate(7) (0.50 g, 1.1 mmol) was then added as a cold solution (0° C.) in THF(5.33 mL). The flask was warmed to room temperature, stirred for 10minutes and then cooled back to 0° C., at which point2-(trimethylsilyl)ethoxymethyl chloride (0.19 mL, 1.1 mmol) was addedvia a syringe. The mixture was slowly warmed to room temperature andallowed to stir for 12 hours. The reaction was incomplete by LCMS. Thereaction mixture was treated with 2-(trimethylsilyl)ethoxymethylchloride (0.09 mL) and heated to 40° C. for 3 hours. It was cooled toroom temperature, quenched with sat'd aqueous NH₄Cl, and extracted withEtOAc (3×). The organic solution was washed with brine, dried overMgSO₄, and concentrated. The residue was purified by silica gelchromatography (0 to 10% EtOAc in heptane) to afford 104a (0.14 g, 22%yield). MS (ESI+) m/z: [M+H]⁺=599.2/601.2.

Preparation of tert-butyl((2R,5R)-5-(2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2,5-dimethyl-2-(trifluoromethyl)-5,6-dihydro-2H-1,4-oxazin-3-yl)((2-(trimethylsilyl)ethoxy)methyl)carbamate(104b)

Boronic ester 104b (82 mg, 54% yield) was prepared as an off-whiteamorphous solid in a manner analogous to that employed for thepreparation of boronic ester 103a, here using tert-butyl((2R,5R)-5-(5-bromo-2-fluorophenyl)-2,5-dimethyl-2-(trifluoromethyl)-5,6-dihydro-2H-1,4-oxazin-3-yl)((2-(trimethylsilyl)ethoxy)methyl)carbamate(104a) (0.14 g, 0.23 mmol), bis(pinacolato)diboron (Sigma-Aldrich, St.Louis, Mo., USA, 0.12 g, 0.47 mmol), potassium acetate (Sigma-Aldrich,St. Louis, Mo., USA, 69 mg, 0.70 mmol), and1,1′-bis(diphenylphosphino)ferrocene palladium(II) dichloridedichloromethane adduct (Strem Chemicals, Inc., Newburyport, Mass., USA)(0.010 g, 0.012 mmol) as starting materials. MS (ESI+) m/z:[M+H−Boc]=547.3. ¹⁹F NMR (376 MHz, Chloroform-d) δ ppm −79.98-−74.42 (m,3F) −105.61 (s, 1F) −107.77 (s, 1F).

Preparation of6-((Z)-2-(3-((3R,6R)-5-amino-3,6-dimethyl-6-(trifluoromethyl)-3,6-dihydro-2H-1,4-oxazin-3-yl)-4-fluorophenyl)-1-fluorovinyl)nicotinonitrile(104)

Intermediate 104c (0.43 g, 0.64 mmol, 62% yield) as an off-white solidwas prepared via a cross-coupling reaction analogous to that employedfor the preparation of Example 103, here using boronic ester 104b (0.67g, 1.0 mmol), potassium phosphate (Sigma-Aldrich, St. Louis, Mo., USA,0.35 g, 2.6 mmol), (Z)-6-(1-fluoro-2-iodovinyl)nicotinonitrile (3) (0.31g, 1.1 mmol), 1,1-bis[(di-t-butyl-p-methylaminophenyl]palladium(II)chloride (Sigma-Aldrich, St. Louis, Mo., USA, 0.073 g, 0.10 mmol) asstarting materials. MS (ESI+) m/z: [M+H−Boc]⁺=567.3.

A solution of 104c (0.43 g, 0.65 mmol) and p-toluenesulfonic acidmonohydrate (0.37 g, 1.9 mmol) in 1,4-dioxane (3.4 mL) was heated at 85°C. for 2 hours. This mixture was quenched with sat'd aqueous NaHCO₃,extracted with EtOAc, dried over MgSO₄, and concentrated. The crudemixture was purified on a silica gel column (10-20% (3:1 EtOAc/EtOH) inheptane) to give6-((Z)-2-(3-((3R,6R)-5-amino-3,6-dimethyl-6-(trifluoromethyl)-3,6-dihydro-2H-1,4-oxazin-3-yl)-4-fluorophenyl)-1-fluorovinyl)nicotinonitrile(104) (0.04 g, 14% yield) as an off-white amorphous solid. MS (ESI+)m/z: [M+H]⁺=437.1. ¹H NMR (400 MHz, Chloroform-d) δ ppm 8.84 (d, J=1.17Hz, 1H) 8.03 (dd, J=8.31, 2.05 Hz, 1H) 7.81 (dd, J=7.82, 2.15 Hz, 1H)7.64-7.74 (m, 2H) 7.18-7.33 (m, 1H) 7.20 (s, 1H) 7.10 (dd, J=11.74, 8.41Hz, 1H) 3.97-4.14 (m, 2H) 1.59 (s, 3H) 1.51 (s, 3H). One NH proton wasnot observed. ¹⁹F NMR (376 MHz, Chloroform-d) δ ppm −77.28-−72.62 (m,3F) −110.12 (br s, 1F) −125.61 (d, J=38.74 Hz, 1F).

Example 1055-((Z)-2-(3-((3R,6R)-5-amino-3,6-dimethyl-6-(trifluoromethyl)-3,6-dihydro-2H-1,4-oxazin-3-yl)-4-fluorophenyl)-1-fluorovinyl)pyrazine-2-carbonitrile

Preparation of tert-butyl((2R,5R)-5-(5-((Z)-2-(5-chloropyrazin-2-yl)-2-fluorovinyl)-2-fluorophenyl)-2,5-dimethyl-2-(trifluoromethyl)-5,6-dihydro-2H-1,4-oxazin-3-yl)((2-(trimethylsilyl)ethoxy)methyl)carbamate(105a)

This compound (0.62 g, 56% yield) as a yellow oil was prepared using across-coupling reaction similar to that described for the synthesis ofExample 103, here using potassium phosphate (0.56 g, 4.1 mmol),(Z)-2-chloro-5-(1-fluoro-2-iodovinyl)pyrazine (4) (0.51 g, 1.8 mmol),1,1-bis[(di-tert-butyl-p-methylaminophenyl]palladium(II) chloride (0.12g, 0.16 mmol), and boronic ester 104b (1.06 g, 1.64 mmol) as startingmaterials. MS (ESI+) m/z: [M+H−Boc]⁺=577.1. ¹H NMR (400 MHz,Chloroform-d) δ ppm 8.66 (s, 1H) 8.53-8.60 (m, 1H) 7.74 (ddd, J=8.41,4.60, 2.05 Hz, 1H) 7.57-7.65 (m, 1H) 7.12-7.21 (m, 1H) 6.98-7.12 (m, 1H)5.07 (d, J=10.76 Hz, 1H) 4.35 (d, J=10.76 Hz, 1H) 4.23-4.28 (m, 1H) 3.82(d, J=12.32 Hz, 1H) 3.49-3.62 (m, 2H) 1.96 (s, 3H) 1.75 (s, 3H)1.52-1.63 (m, 2H) 1.50 (s, 9H) −0.01-0.01 (m, 9H).

Preparation of5-((Z)-2-(3-((3R,6R)-5-amino-3,6-dimethyl-6-(trifluoromethyl)-3,6-dihydro-2H-1,4-oxazin-3-yl)-4-fluorophenyl)-1-fluorovinyl)pyrazine-2-carbonitrile(105)

A vial was charged with tert-butyl((2R,5R)-5-(5-((Z)-2-(5-chloropyrazin-2-yl)-2-fluorovinyl)-2-fluorophenyl)-2,5-dimethyl-2-(trifluoromethyl)-5,6-dihydro-2H-1,4-oxazin-3-yl)((2-(trimethylsilyl)ethoxy)methyl)carbamate(105a) (0.072 g, 0.11 mmol), zinc cyanide (Sigma-Aldrich, St. Louis,Mo., USA, 0.037 g, 0.32 mmol),2-(dicyclohexylphosphino)-2′,6′-dimethoxy-1,1′-biphenyl (Sigma-Aldrich,St. Louis, Mo., USA, 0.013 g, 0.032 mmol),tris(dibenzylideneacetone)dipalladium (0) (Strem Chemicals, Inc.,Newburyport, Mass., USA, 0.015 g, 0.016 mmol), and N,N-dimethylacetamide (1.0 mL). The vial was evacuated and backfilled withnitrogen. The mixture was heated at 100° C. for 2 hours. The mixture wascooled, filtered through a pad of celite and the cake washed with EtOAc(2 mL). The filtrate was washed with water (5 mL) and brine (5 mL),dried over Na₂SO₄ and concentrated in vacuo. The resulting crude residuewas purified by silica gel chromatography (0 to 15% gradient of EtOAc inheptane) to provide tert-butyl((2R,5R)-5-(5-((Z)-2-(5-cyanopyrazin-2-yl)-2-fluorovinyl)-2-fluorophenyl)-2,5-dimethyl-2-(trifluoromethyl)-5,6-dihydro-2H-1,4-oxazin-3-yl)((2-(trimethylsilyl)ethoxy)methyl)carbamate(105b) (0.052 g, 73% yield) as a yellow solid.

5-((Z)-2-(3-((3R,6R)-5-Amino-3,6-dimethyl-6-(trifluoromethyl)-3,6-dihydro-2H-1,4-oxazin-3-yl)-4-fluorophenyl)-1-fluorovinyl)pyrazine-2-carbonitrile(Example 105) (3.9 mg, 35% yield) as an off-white solid was prepared ina manner similar to that described for Example 104, here starting withp-toluenesulfonic acid monohydrate (15 mg, 0.076 mmol) and 105b (17 mg).MS (ESI+) m/z: [M+H]⁺=438.1. ¹H NMR (400 MHz, Chloroform-d) δ ppm9.53-9.64 (m, 1H) 8.96 (s, 1H) 8.82-8.86 (m, 1H) 7.99 (br s, 1H) 7.84(dd, J=7.92, 2.25 Hz, 1H) 7.69 (ddd, J=8.46, 4.65, 2.35 Hz, 1H)7.18-7.32 (m, 1H) 7.11 (dd, J=11.64, 8.51 Hz, 1H) 3.99-4.11 (m, 2H) 1.58(d, J=0.98 Hz, 3H) 1.50 (s, 3H). ¹⁹F NMR (376 MHz, Chloroform-d) δ ppm−77.43-75.02 (m, 3F) −108.90 (d, J=2.38 Hz, 1F) −128.86-−127.80 (m, 1F).

Example 106(2R,5R)-5-(2-fluoro-5-((Z)-2-fluoro-2-(5-(2,2,3,3-tetrafluoropropoxy)pyrazin-2-yl)vinyl)phenyl)-2,5-dimethyl-2-(trifluoromethyl)-5,6-dihydro-2H-1,4-oxazin-3-amine

A flask was charged with 2,2,3,3-tetrafluoropropanol (Sigma-Aldrich, St.Louis, Mo., USA, 0.09 mL, 0.67 mmol), cesium carbonate (130 mg, 0.40mmol) and(2R,5R)-5-(5-((Z)-2-(5-chloropyrazin-2-yl)-2-fluorovinyl)-2-fluorophenyl)-2,5-dimethyl-2-(trifluoromethyl)-5,6-dihydro-2H-1,4-oxazin-3-amine(108) (0.060 g, 0.13 mmol) and THF (2.69 mL). The mixture was heated to50° C. and reaction progress monitored by LCMS. Upon consumption of thestarting material, the mixture was filtered through a pad of celite,concentrated and purified by silica gel chromatography using a gradientof EtOAc/EtOH (3:1) in heptane (0 to 50%) to afford Example 106 (58 mg,80% yield) as an off-white solid. MS (ESI+) m/z: [M+H]⁺=543.2. ¹H NMR(400 MHz, Chloroform-d) δ ppm 8.37 (s, 1H) 8.30 (s, 1H) 7.75 (dd,J=7.82, 2.15 Hz, 1H) 7.60-7.69 (m, 1H) 7.06 (dd, J=11.74, 8.61 Hz, 1H)6.80-6.97 (m, 1H) 5.84-6.17 (m, 1H) 4.81 (t, J=12.62 Hz, 2H) 3.92-4.13(m, 2H) 1.57 (s, 3H) 1.46-1.52 (m, 3H). NH₂ peak was not observed.

Example 107(2R,5R)-5-(2-fluoro-5-((Z)-2-fluoro-2-(5-(prop-2-yn-1-yloxy)pyrazin-2-yl)vinyl)phenyl)-2,5-dimethyl-2-(trifluoromethyl)-5,6-dihydro-2H-1,4-oxazin-3-amine

This compound (32 mg, 50% yield) as an off-white solid was prepared viaa protocol analogous to that employed in the synthesis of Example 106,here using Example 108 (62 mg, 0.14 mmol), cesium carbonate (136 mg,0.410 mmol) and propargyl alcohol (Sigma-Aldrich, St. Louis, Mo., USA,39 mg, 0.69 mmol) as starting materials. MS (ESI+) m/z: [M+H]⁺=467.2. ¹HNMR (400 MHz, Chloroform-d) δ ppm 8.37 (s, 1H) 8.25 (s, 1H) 7.74 (dd,J=7.82, 2.15 Hz, 1H) 7.53-7.66 (m, 1H) 7.05 (dd, J=11.83, 8.51 Hz, 1H)6.72-6.93 (m, 1H) 5.03 (d, J=2.35 Hz, 2H) 4.21-4.86 (m, 1H) 3.89-4.12(m, 2H) 2.47-2.59 (m, 1H) 1.57 (s, 3H) 1.45-1.53 (m, 3H) 1.45-1.53 (m,1H).

Example 108(2R,5R)-5-(5-((Z)-2-(5-chloropyrazin-2-yl)-2-fluorovinyl)-2-fluorophenyl)-2,5-dimethyl-2-(trifluoromethyl)-5,6-dihydro-2H-1,4-oxazin-3-amine

This compound (165 mg, 72% yield) as an off-white solid was prepared ina manner similar to that described for the synthesis of Example 105,here using 105a (0.35 mg, 0.52 mmol) and p-toluenesulfonic acidmonohydrate (295 mg, 1.55 mmol) as starting materials. MS (ESI+) m/z:[M+H]⁺=447.0. ¹H NMR (400 MHz, Chloroform-d) δ ppm 8.64 (s, 1H) 8.55 (s,1H) 7.80-7.91 (m, 1H) 7.61-7.72 (m, 1H) 6.97-7.13 (m, 3H) 5.33 (br s,1H) 3.99 (d, J=8.61 Hz, 1H) 3.70-3.78 (m, 1H) 1.61 (s, 3H) 1.60 (s, 2H)1.59-1.60 (m, 1H). ¹⁹F NMR (376 MHz, Chloroform-d) δ ppm −75.00 (s, 3F)−75.90 (br s, 1F) −110.86 (d, J=115.63 Hz, 1F).

Example 1096-((Z)-2-(3-((4R,5R)-2-amino-4-methyl-5-(2,2,2-trifluoroethoxy)-5,6-dihydro-4H-1,3-oxazin-4-yl)-4-fluorophenyl)-1-fluorovinyl)nicotinonitrile

Preparation ofdi-Boc-(4R,5R)-4-(5-bromo-2-fluorophenyl)-4-methyl-5-(2,2,2-trifluoroethoxy)-5,6-dihydro-4H-1,3-oxazin-2-amine(109a)

A mixture of(4R,5R)-4-(5-bromo-2-fluorophenyl)-4-methyl-5-(2,2,2-trifluoroethoxy)-5,6-dihydro-4H-1,3-oxazin-2-amine(6) (2.39 g, 6.21 mmol), di-tert-butyl dicarbonate (3.39 g, 15.5 mmol),N,N-dimethylpyridin-4-amine (0.379 g, 3.10 mmol), andN-ethyl-N-isopropylpropan-2-amine (3.24 mL, 18.6 mmol) in DCM (25 mL)was stirred at room temperature overnight. The mixture was concentratedin vacuo and purified by silica gel chromatography (0-100% EtOAc inhexanes) to give 109a (2.89 g, 80% yield) as a white solid. MSm/z=585/587 [M+H]⁺. ¹H NMR (400 MHz, Chloroform-d) δ 7.66 (dd, J=2.54,7.04 Hz, 1H), 7.36-7.45 (m, 1H), 6.95 (dd, J=8.71, 11.84 Hz, 1H), 4.25(dd, J=2.84, 12.03 Hz, 1H), 4.15 (s, 1H), 4.01 (q, J=8.41 Hz, 2H), 3.86(d, J=11.74 Hz, 1H), 1.67 (s, 3H), 1.51-1.61 (m, 18H).

Preparation of6-((Z)-2-(3-((4R,5R)-2-amino-4-methyl-5-(2,2,2-trifluoroethoxy)-5,6-dihydro-4H-1,3-oxazin-4-yl)-4-fluorophenyl)-1-fluorovinyl)nicotinonitrile(109)

A mixture ofdi-Boc-(4R,5R)-4-(5-bromo-2-fluorophenyl)-4-methyl-5-(2,2,2-trifluoroethoxy)-5,6-dihydro-4H-1,3-oxazin-2-amine(109a) (2.06 g, 3.52 mmol), bis(pinacolato)diboron (1.16 g, 4.57 mmol),potassium acetate (1.38 g, 14.1 mmol) and 1,4-dioxane (30 mL) was purgedwith argon, then[1,1′-bis(diphenylphosphino)ferrocene]-dichloropalladium(II) complexwith DCM (0.17 g, 0.21 mmol) was added. The mixture was heated at 90° C.for 1 hour. It was filtered through celite and the cake was washed withEtOAc. The filtrate was concentrated in vacuo to give boronic ester 109bwhich was used in next step without purification. MS m/z=633 [M+H]⁺.

A mixture of the boronic ester 109b (0.10 g, 0.16 mmol),(Z)-6-(1-fluoro-2-iodovinyl)nicotinonitrile (3) (65 mg, 0.24 mmol),potassium phosphate (0.10 g, 0.47 mmol),bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II)(0.011 g, 0.016 mmol),1,4-dioxane (1.4 mL) and water (0.2 mL) was purgedwith argon, then the vial was sealed and heated at 80° C. for 1 hour.The mixture was diluted with water and extracted with EtOAc. The organicsolution was dried over Na₂SO₄, and concentrated in vacuo. The crude waspurified by silica gel chromatography (0-50% EtOAc in heptane) to givetert-butyl((4R,5R)-4-(5-((Z)-2-(5-cyanopyridin-2-yl)-2-fluorovinyl)-2-fluorophenyl)-4-methyl-5-(2,2,2-trifluoroethoxy)-5,6-dihydro-4H-1,3-oxazin-2-yl)carbamateas an off-white solid. MS m/z=453.2 [M+H]⁺. The off-white solid wastreated with DCM (2 mL) and TFA (1 mL) and stirred at room temperaturefor 30 minutes. The mixture was concentrated in vacuo and the residuewas partitioned between EtOAc and saturated aqueous Na₂CO₃. The organicsolution was dried over Na₂SO₄, and concentrated in vacuo. The crude waspurified by silica gel chromatography (0 to 100% EtOAc/EtOH (3/1 v/v) inheptane) to provide6-((Z)-2-(3-((4R,5R)-2-amino-4-methyl-5-(2,2,2-trifluoroethoxy)-5,6-dihydro-4H-1,3-oxazin-4-yl)-4-fluorophenyl)-1-fluorovinyl)nicotinonitrile(109) as a white solid (56 mg, 78% yield). MS m/z=453.2 [M+H]⁺. ¹H NMR(400 MHz, Chloroform-d) δ 8.84 (s, 1H), 8.03 (d, J=8.41 Hz, 1H),7.66-7.80 (m, 3H), 7.25 (d, J=38.15 Hz, 1H), 7.09 (dd, J=8.41, 11.74 Hz,1H), 3.99-4.22 (m, 4H), 3.80 (d, J=11.93 Hz, 1H), 1.67 (s, 3H). NH₂ wasnot clear in NMR. ¹⁹F NMR (376 MHz, Chloroform-d) δ −74.32 (t, J=8.24Hz, 3F), −109.17 (br. s., 1F), −124.83 (d, J=36.41 Hz, 1F).

Example 110(4R,5R)-4-(5-((Z)-2-(5-chloropyrazin-2-yl)-2-fluorovinyl)-2-fluorophenyl)-4-methyl-5-(2,2,2-trifluoroethoxy)-5,6-dihydro-4H-1,3-oxazin-2-amine

This compound (0.38 g, 52% overall yield) as an off-white solid wasprepared in a fashion similar to that described for Example 109, herestarting with (Z)-2-chloro-5-(1-fluoro-2-iodovinyl)pyrazine (4) (0.67 g,2.37 mmol) and boronic ester 109b (1.00 g, 1.58 mmol). MS m/z=463[M+H]⁺. ¹H NMR (400 MHz, Chloroform-d) δ 8.63 (s, 1H), 8.55 (s, 1H),7.65-7.77 (m, 2H), 6.94-7.16 (m, 2H), 4.19 (s, 1H), 3.98-4.16 (m, 3H),3.79 (d, J=11.74 Hz, 1H), 1.66 (s, 3H). NH₂ was not clear in NMR. ¹⁹FNMR (376 MHz, Chloroform-d) δ −74.33 (t, J=8.67 Hz, 3F), −109.52 (br.s., 1F), −126.15 (d, J=39.01 Hz, 1F).

Example 111(4R,5R)-4-(2-fluoro-5-((Z)-2-fluoro-2-(5-(prop-2-yn-1-yloxy)pyrazin-2-yl)vinyl)phenyl)-4-methyl-5-(2,2,2-trifluoroethoxy)-5,6-dihydro-4H-1,3-oxazin-2-amine

A mixture of(4R,5R)-4-(5-((Z)-2-(5-chloropyrazin-2-yl)-2-fluorovinyl)-2-fluorophenyl)-4-methyl-5-(2,2,2-trifluoroethoxy)-5,6-dihydro-4H-1,3-oxazin-2-amine(110) (60 mg, 0.13 mmol), cesium carbonate (130 mg, 0.39 mmol), andpropargyl alcohol (TCI America, Portland, Oreg., USA) (38 μL, 0.65 mmol)in THF (1.5 mL) was stirred at room temperature overnight. The mixturewas diluted with water and extracted with EtOAc. The organic solutionwas dried over Na₂SO₄, and concentrated in vacuo. The crude was purifiedby silica gel chromatography (0-100% EtOAc/EtOH (3/3 v/v) in heptane) toafford the title compound (52 mg, 83% yield) as an off-white solid. MSm/z=483 [M+H]⁺. ¹H NMR (400 MHz, Chloroform-d) δ 8.39 (s, 1H), 8.26 (s,1H), 7.68 (d, J=7.24 Hz, 2H), 7.05 (dd, J=8.90, 11.64 Hz, 1H), 6.76-6.92(m, 1H), 5.04 (d, J=2.35 Hz, 2H), 4.18 (s, 1H), 4.00-4.13 (m, 3H), 3.79(d, J=11.74 Hz, 1H), 2.49-2.57 (m, 1H), 1.65 (s, 3H). NH₂ was not clearin NMR. ¹⁹F NMR (376 MHz, Chloroform-d) δ −74.34 (t, J=8.67 Hz, 3F),−110.92 (br. s., 1F), −125.16 (d, J=39.88 Hz, 1F).

Example 1125-((Z)-2-(3-((4R,5R)-2-amino-4-methyl-5-(2,2,2-trifluoroethoxy)-5,6-dihydro-4H-1,3-oxazin-4-yl)-4-fluorophenyl)-1-fluorovinyl)pyrazine-2-carbonitrile

This compound (45 mg, 62% overall yield) as an off-white solid wasprepared in a fashion similar to that described for Example 109, herestarting with (Z)-5-(1-fluoro-2-iodovinyl)pyrazine-2-carbonitrile (5)(65 mg, 0.23 mmol) and boronic ester 109b (100 mg, 016 mmol). MS m/z=454[M+H]⁺. ¹H NMR (400 MHz, Chloroform-d) δ 8.96 (s, 1H), 8.84 (s, 1H),7.69-7.82 (m, 2H), 7.26 (d, J=38.54 Hz, 1H), 7.11 (dd, J=8.51, 11.84 Hz,1H), 3.98-4.23 (m, 4H), 3.79 (d, J=12.13 Hz, 1H), 1.66 (s, 3H). NH₂ wasnot clear in NMR. ¹⁹F NMR (376 MHz, Chloroform-d) δ −74.31 (t, J=8.67Hz, 3F), −107.92 (br. s., 1F), −127.40 (d, J=38.15 Hz, 1F).

Example 113(4R,5R)-4-(5-((Z)-2-(5-(but-2-yn-1-yloxy)pyrazin-2-yl)-2-fluorovinyl)-2-fluorophenyl)-4-methyl-5-(2,2,2-trifluoroethoxy)-5,6-dihydro-4H-1,3-oxazin-2-amine

This compound (40 mg, 57% yield) as an off-white solid was prepared in afashion similar to that described for Example 111, here starting withbut-2-yn-1-ol (Sigma-Aldrich, 49 mg, 0.70 mmol) and Example 110 (65 mg,0.14 mmol). MS m/z=497 [M+H]⁺. ¹H NMR (400 MHz, Chloroform-d) δ 8.39 (s,1H), 8.25 (s, 1H), 7.67 (d, J=10.17 Hz, 2H), 7.05 (dd, J=9.29, 11.64 Hz,1H), 6.75-6.93 (m, 1H), 4.99 (d, J=1.96 Hz, 2H), 4.19 (s, 1H), 4.11 (d,J=11.93 Hz, 1H), 3.99-4.08 (m, 2H), 3.80 (d, J=11.93 Hz, 1H), 1.89 (s,3H), 1.66 (s, 3H). NH₂ was not clear in NMR. ¹⁹F NMR (376 MHz,Chloroform-d) δ −74.34 (t, J=8.67 Hz, 3F), −111.05 (br. s., 1F), −125.03(d, J=40.75 Hz, 1F).

Example 114(R,Z)-6-(2-(3-(2-amino-5,5-difluoro-4-methyl-5,6-dihydro-4H-1,3-oxazin-4-yl)-4-fluorophenyl)-1-fluorovinyl)nicotinonitrile

Preparation ofdi-Boc-(R)-4-(5-bromo-2-fluorophenyl)-5,5-difluoro-4-methyl-5,6-dihydro-4H-1,3-oxazin-2-amine(114a)

To a mixture of(R)-4-(5-bromo-2-fluorophenyl)-5,5-difluoro-4-methyl-5,6-dihydro-4H-1,3-oxazin-2-amine(prepared according to the procedures described in WO 2012156284) (1.80g, 5.57 mmol), N,N-dimethylpyridin-4-amine (0.34 g, 2.8 mmol) andN-ethyl-N-isopropylpropan-2-amine (2.91 mL, 16.7 mmol) in DCM (18 mL)was added di-tert-butyl dicarbonate (3.04 g, 13.9 mmol) at roomtemperature. The resulting mixture was stirred overnight. It waspartitioned between DCM and sat'd aqueous NaHCO₃. The aqueous layer wasback extracted with DCM (2×) and the combined organic solution was dried(Na₂SO₄) and concentrated to give 114a as an off-white solid which wasused as crude in the next step. MS (ESI, positive ion) m/z:=523.1/525.1(M+1)⁺.

Preparation ofdi-Boc-(R)-5,5-difluoro-4-(2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-4-methyl-5,6-dihydro-4H-1,3-oxazin-2-amine(114b)

A stream of nitrogen was bubbling through a mixture of 114a (2.92 g,5.58 mmol), 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane)(2.12 g, 8.37 mmol),(1,1′-bis(diphenylphosphino)ferrocene)dichloropalladium(II) (0.41 g,0.56 mmol) and potassium acetate (1.92 g, 19.5 mmol) in 1,4-dioxane (28mL) for 10 minutes. The mixture was heated at 90° C. for 48 hours. Aftercooling to room temperature the mixture was filtered through a pad ofcelite and the cake washed with 3:7 ethyl acetate/heptane. The filtratewas concentrated and the residue was purified on a silica gel column(0-40% ethyl acetate in heptane) to give 114b (1.40 g, 44% yield) as awhite solid. MS (ESI, positive ion) m/z:=571.3 (M+1).

Preparation ofdi-Boc-(R,Z)-6-(2-(3-(2-amino-5,5-difluoro-4-methyl-5,6-dihydro-4H-1,3-oxazin-4-yl)-4-fluorophenyl)-1-fluorovinyl)nicotinonitrile(114c)

A mixture of boronic ester 114b (180 mg, 0.316 mmol),(Z)-6-(1-fluoro-2-iodovinyl)nicotinonitrile (3) (104 mg, 0.38 mmol),potassium phosphate tribasic (167 mg, 0.789 mmol), and1,1-bis[(di-t-butyl-p-methylaminophenyl]palladium(II) chloride (22 mg,0.032 mmol) was placed under nitrogen atmosphere using 3evacuation/backfill cycles. Dioxane (1.8 mL) and water (0.4 mL) wereadded and the mixture was heated to 80° C. for 2 hours. The mixture wascooled to room temperature and partitioned between EtOAc and water. Thelayers were separated and the organic layer was dried (Na₂SO₄),filtered, and concentrated in vacuo. The crude product was purified bysilica gel chromatography (0 to 20% EtOAc in heptane) to give 114c (143mg, 77% yield) as a tan foam. MS (ESI, positive ion) m/z:=591.2 (M+1).

Preparation of(R,Z)-6-(2-(3-(2-amino-5,5-difluoro-4-methyl-5,6-dihydro-4H-1,3-oxazin-4-yl)-4-fluorophenyl)-1-fluorovinyl)nicotinonitrile(114)

A mixture of 114c (143 mg, 0.24 mmol) in DCM (1.2 mL) andtrifluoroacetic acid (0.4 mL) was stirred at room temperature for 1hour. The solvent was evaporated to dryness and the residue wasazeotroped with DCM (2×), then partitioned between DCM and saturatedNaHCO₃. The aqueous layer was back extracted with DCM (2×) and thecombined organic layers were dried (Na₂SO₄) and concentrated. The crudematerial was purified by chromatography through a Biotage 10 g ultracolumn (0 to 30% 3:1 EtOAc/EtOH in heptane) to provide(R,Z)-6-(2-(3-(2-amino-5,5-difluoro-4-methyl-5,6-dihydro-4H-1,3-oxazin-4-yl)-4-fluorophenyl)-1-fluorovinyl)nicotinonitrile(114) (75 mg, 79% yield) as an off-white solid. MS (ESI, positive ion)m/z:=391.1 (M+1)⁺. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 9.08 (1H, s), 8.45(1H, dd, J=8.31, 2.05 Hz), 8.01 (1H, dd, J=7.73, 2.25 Hz), 7.86 (1H, d,J=8.02 Hz), 7.77 (1H, ddd, J=8.36, 4.35, 2.35 Hz), 7.24-7.29 (1H, m),7.30 (1H, d, J=40 Hz), 5.97 (2H, s), 4.32-4.42 (1H, m), 4.06 (1H, td,J=12.52, 7.83 Hz), 1.66 (3H, s). ¹⁹F NMR (376 MHz, DMSO-d₆) δ ppm−106.24 (1F, br dd, J=32.08, 17.34 Hz), −113.28-112.09 (1F, m), −116.68(1F, dd, J=247.95, 32.08 Hz), −124.45 (1F, s).

Example 115(R,Z)-5,5-difluoro-4-(2-fluoro-5-(2-fluoro-2-(5-(prop-2-yn-1-yloxy)pyrazin-2-yl)vinyl)phenyl)-4-methyl-5,6-dihydro-4H-1,3-oxazin-2-amine

Preparation ofdi-Boc-(R,Z)-4-(5-(2-(5-chloropyrazin-2-yl)-2-fluorovinyl)-2-fluorophenyl)-5,5-difluoro-4-methyl-5,6-dihydro-4H-1,3-oxazin-2-amine(115a)

A mixture of 114b (200 mg, 0.35 mmol),(Z)-2-chloro-5-(1-fluoro-2-iodovinyl)pyrazine (4) (120 mg, 0.42 mmol),potassium phosphate tribasic (190 mg, 0.88 mmol), and1,1-bis[(di-t-butyl-p-methylaminophenyl]palladium(II) chloride (25 mg,0.035 mmol) was placed under nitrogen atmosphere using 3evacuation/backfill cycles. Dioxane (1.8 mL) and water (0.37 mL) wereadded and the mixture was heated to 80° C. for 2 hours. The mixture wascooled to room temperature and partitioned between EtOAc and water. Thelayers were separated and the organic layer was concentrated in vacuo.The crude product was purified by silica gel chromatography (0 to 20%EtOAc/heptane) to give 115a (189 mg, 90% yield) as a light yellow foam.MS (ESI, positive ion) m/z:=623.2 (M+Na).

Preparation of(R,Z)-5,5-difluoro-4-(2-fluoro-5-(2-fluoro-2-(5-(prop-2-yn-1-yloxy)pyrazin-2-yl)vinyl)phenyl)-4-methyl-5,6-dihydro-4H-1,3-oxazin-2-amine(115)

To 115a (190 mg, 0.31 mmol) dissolved in DCM (1.6 mL) was addedtrifluoroacetic acid (0.5 mL). The reaction mixture was stirred at roomtemperature for 1 hours. The solvent was evaporated to dryness and theresidue was azeotroped with DCM (2×), then partitioned between DCM andsaturated NaHCO₃. The aqueous layer was back extracted with DCM (2×) andthe combined organic layers were and concentrated to give an orange oilthat contained 115b which was used as crude. To the crude material of115b (130 mg, 0.31 mmol) in DMF (0.8 mL) was added propargyl alcohol (94μL, 1.6 mmol) followed by cesium carbonate (256 mg, 0.790 mmol). Thereaction mixture was stirred at room temperature for 16 hours. It waspartitioned between EtOAc and brine. The aqueous layer was backextracted with EtOAc (2×) and the combined organics was dried over MgSO₄and concentrated. The crude material was purified by silica gelchromatography (0 to 40% 3:1 EtOAc/EtOH in heptane) to provide(R,Z)-5,5-difluoro-4-(2-fluoro-5-(2-fluoro-2-(5-(prop-2-yn-1-yloxy)pyrazin-2-yl)vinyl)phenyl)-4-methyl-5,6-dihydro-4H-1,3-oxazin-2-amine(115) (61 mg, 46% yield) as a light yellow solid. MS (ESI, positive ion)m/z:=421.1 (M+1). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.51 (1H, s), 8.46(1H, s), 7.93 (1H, dd, J=7.63, 2.15 Hz), 7.69 (1H, ddd, J=8.36, 4.45,2.45 Hz), 7.23 (1H, dd, J=12.03, 8.51 Hz), 6.92 (1H, d, J=40 Hz), 5.95(2H, s), 5.08 (2H, d, J=2.54 Hz), 4.30-4.42 (1H, m), 4.00-4.10 (1H, m),2.51 (1H, s), 1.65 (3H, s). ¹⁹F NMR (376 MHz, DMSO-d₆) ppm −107.63 (1F,dd, J=31.21, 18.21 Hz), −113.50-−112.21 (1F, m), −116.70 (1F, dd,J=247.96, 31.21 Hz), −124.73 (1F, s).

Example 116(R,Z)-6-(2-(6-(2-amino-5,5-difluoro-4-methyl-5,6-dihydro-4H-1,3-oxazin-4-yl)-5-fluoropyridin-2-yl)-1-fluorovinyl)nicotinonitrile

Preparation ofdi-Boc-(R)-4-(6-bromo-3-fluoropyridin-2-yl)-5,5-difluoro-4-methyl-5,6-dihydro-4H-1,3-oxazin-2-amine(116b)

To a mixture of(R)-4-(6-bromo-3-fluoropyridin-2-yl)-5,5-difluoro-4-methyl-5,6-dihydro-4H-1,3-oxazin-2-amine(116a, prepared according to the methods described in WO2013027188) (3.0g, 9.3 mmol), N,N-dimethylpyridin-4-amine (565 mg, 4.6 mmol) andN-ethyl-N-isopropylpropan-2-amine (4.83 ml, 27.8 mmol) in DCM (31 mL)was added di-tert-butyl dicarbonate (5.0 g, 23.1 mmol). The resultingmixture was allowed to stir at room temperature for 3 hours thenpartitioned between DCM (100 mL) and sat'd aqueous NaHCO₃ (50 mL). Theaqueous layer was back extracted with DCM (100 mL) and the combinedorganic solution was dried over Na₂SO₄ and concentrated. The crudematerial was purified by silica gel chromatography (0 to 30% of (3:1)EtOAc/EtOH in heptane) to give 116b (4.4 g, 91% yield) as white solid.MS (ESI, positive ion) m/z:=524.0/526.0 (M+1)⁺.

Preparation ofdi-Boc-(R)-5,5-difluoro-4-(3-fluoro-6-(trimethylstannyl)pyridin-2-yl)-4-methyl-5,6-dihydro-4H-1,3-oxazin-2-amine(116c)

A solution of 116b (183 mg, 0.35 mmol) and hexamethylditin (73 μL, 0.35mmol) in 1,2-dimethoxyethane (1.7 mL) was degassed under a flow of argonfor 5 minutes then treated with tetrakis(triphenylphosphine)palladium(0)(20 mg, 0.02 mmol) and stirred at 80° C. for 16 hours. After cooling toroom temperature, the reaction mixture was filtered through celite andthe filter cake was washed with DME (2×3 mL). The filtrate wasconcentrated to give 116c as a yellow solid which was used directly inthe following step. MS (ESI, positive ion) m/z:=610.1 (M+1)⁺.

Preparation ofdi-Boc-(R,Z)-6-(2-(6-(2-amino-5,5-difluoro-4-methyl-5,6-dihydro-4H-1,3-oxazin-4-yl)-5-fluoropyridin-2-yl)-1-fluorovinyl)nicotinonitrile(116d)

A mixture of 116c (212 mg, 0.35 mmol),(Z)-6-(1-fluoro-2-iodovinyl)nicotinonitrile (115 mg, 0.42 mmol),potassium phosphate tribasic (185 mg, 0.87 mmol) and1,1-bis[(di-t-butyl-p-methylaminophenyl]palladium(ii) chloride (25 mg)was placed under a nitrogen atmosphere using 2 evacuation/backfillcycles. Dioxane (1.8 mL) and water (0.4 mL) were added and the mixturewas heated to 80° C. for 5 hours. The mixture was cooled to roomtemperature and the partitioned between EtOAc and water. The layers wereseparated and the aqueous layer was extracted with EtOAc (2×). Theorganic solution was dried over Na₂SO₄, filtered, and concentrated invacuo. The resulting oil was purified by silica gel chromatography (0 to25% EtOAc in heptane) to give 116d (77 mg, 37% yield) as a light-pinksolid. MS (ESI, positive ion) m/z:=592.3 (M+1)⁺.

Preparation of(R,Z)-6-(2-(6-(2-amino-5,5-difluoro-4-methyl-5,6-dihydro-4H-1,3-oxazin-4-yl)-5-fluoropyridin-2-yl)-1-fluorovinyl)nicotinonitrile(116)

A solution of 116d (77 mg, 0.13 mmol) in DCM (1.2 mL) andtrifluoroacetic acid (0.4 mL) was stirred at room temperature for 1hour. The mixture was evaporated and to the residue was added DCM andevaporated again. The process was repeated twice. The residue waspartitioned between DCM and sat'd aqueous NaHCO₃. The aqueous layer wasextracted with DCM (2×) and the combined organic solution wasconcentrated. The crude material was purified by silica gelchromatography (0 to 50% of (3:1) EtOAc/EtOH in heptane) to provide(R,Z)-6-(2-(6-(2-amino-5,5-difluoro-4-methyl-5,6-dihydro-4H-1,3-oxazin-4-yl)-5-fluoropyridin-2-yl)-1-fluorovinyl)nicotinonitrile(116) (30 mg, 59% yield) as an off-white solid. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 9.12 (1H, s), 8.49 (1H, dd, J=8.31, 2.05 Hz), 7.93 (2H,t, J=7.56 Hz), 7.76 (1H, dd, J=11.35, 8.61 Hz), 7.32 (1H, d, J=40 Hz),5.77 (2H, s), 4.16-4.39 (2H, m), 1.70 (3H, s). ¹⁹F NMR (376 MHz,DMSO-d₆) δ ppm −114.56 (2F, d, J=11.27 Hz), −115.32 (1F, br t, J=11.27Hz), −120.57 (1F, s). MS (ESI, positive ion) m/z:=392.1 (M+1)⁺.

Example 1176-((Z)-2-(6-((3R,6R)-5-amino-3,6-dimethyl-6-(trifluoromethyl)-3,6-dihydro-2H-1,4-oxazin-3-yl)-5-fluoropyridin-2-yl)-1-fluorovinyl)nicotinonitrile

A glass tube was charged with boronic ester 9 (87 mg, 0.319 mmol),tert-butyl((2R,5R)-5-(6-bromo-3-fluoropyridin-2-yl)-2,5-dimethyl-2-(trifluoromethyl)-5,6-dihydro-2H-1,4-oxazin-3-yl)carbamate(10) (100 mg, 0.21 mmol), cesium carbonate (208 mg, 0.64 mmol),1,4-dioxane (0.6 mL) and water (0.2 mL). The mixture was purged for 5minutes with nitrogen, then treated with PdCl₂(dppf)-CH₂Cl₂ adduct (17mg, 0.02 mmol). The tube was sealed then heated at 80° C. for 16 hours.The reaction mixture was diluted with water (2 mL) and extracted withethyl acetate (5 mL×2). The combined organic solution was dried overNa₂SO₄ and concentrated under reduced pressure. The residue was purifiedby mass triggered preparative HPLC [column: water X-bridge (19×50 mm):mobile phase A: NH₄OAc in water; mobile phase B: 100% ACN; flow rate: 15mL/min] to yield the title compound 117 (15 mg, 16% yield) as a brownsolid. MS (ESI positive ion) m/z: 438.2 (M+H). ¹H NMR (400 MHz, DMSO-d₆)δ 9.12 (d, J=2.1 Hz, 1H), 8.49 (dd, J=8.3, 2.2 Hz, 1H), 8.01-7.85 (m,2H), 7.81-7.69 (m, 1H), 7.37-7.27 (m, 1H), 5.92 (br. s, 2H), 4.17 (d,J=11.7 Hz, 1H), 3.80 (d, J=11.8 Hz, 1H), 1.52 (d, J=5.1 Hz, 6H).

Biological Evaluation

Provided in this section is the biological evaluation of the specificexamples provided herein. In particular, Table 2 contains biologicalactivity data. The data presented in Table 2 provides the IC₅₀ (μM) forthe specific examples obtained in a BACE1 enzyme assay, BACE1 cellassay, BACE2 enzyme assay and CatD assay.

TABLE 2 BACE1 BACE1 BACE2 CatD Enzyme Cell Enzyme Enzyme Ex. No. IC₅₀(μM) IC₅₀ (μM) IC₅₀ (μM) IC₅₀ (μM) 100 0.257 0.948 0.564 63.9 101 0.9541.120 0.421 215.1 102 0.152 0.344 1.62 222.4 103 0.065 0.693 0.017 19.2104 0.026 0.152 0.095 204 105 0.046 0.130 0.273 414.9 106 0.666 4.131.59 88.4 107 0.050 0.112 0.375 82.5 108 0.118 0.663 0.033 39.3 1090.125 0.014 3.87 1186.5 110 0.341 0.090 1.505 524.2 111 0.152 0.059 16664.3 112 0.119 0.027 6.355 970.5 113 0.052 0.048 17.05 233 114 0.2562.66 2.73 >400.0 115 0.283 4.665 5.84 119 116 1.05 0.676 11.4 >400.0 1170.149 0.090 0.853 121

The results presented in Table 2 have been generated with the in vitroassays described below. These assays may be used to test any of thecompounds described herein to assess and characterize a compound'sability to modulate BACE activity and to regulate the cleavage of Aβprecursor protein, thereby reducing or inhibiting the production of Aβprotein.

In Vitro Enzymatic BACE1 and BACE2 FRET (Fluorescence Resonance EnergyTransfer) Assays

The cDNAs for both human recombinant BACE1 and 2 with C-terminal 6-HisTags were cloned into transient protein expression vectors, which weresubsequently transfected into mammalian cell lines. These recombinantproteins were further purified using Ni-NTA affinity chromatography(Qiagen). The assay buffer used in these screens was 0.05 M acetate, pH4.5, 8% DMSO final, 100 μM genapol (which is a nonionic detergent, belowits Critical Micelle Concentration). The β-secretase enzyme (0.02 nM forBACE1 and 0.64 nM for BACE2), which was pre-incubated for one hour withthe test compound, typically in about 1 uL of DMSO according to a serialdilution, was added thereto. The assay was effectively started by theaddition of FRET substrate (50 nM) and the combination was incubated forone hour. The FRET assay was terminated by the addition of tris buffer,which raised the pH to neutrality, and the fluorescence was determined.The FRET substrate was a peptide with commercially available fluorophoreand quencher, on opposite sides of the BACE cleavage site. The specificFRET substrate used in this assay was made by Amgen in-house.Commercially available FRET substrates, for example, the FRET substrateoffered with the BACE1 FRET Assay Kit sold by ThermoFisher Scientific(Catalog Number P2985), may be used in this assay with the appropriatemodifications, which are within the purview of the ability of a personwith ordinary skill in the art. Proteolytic cleavage of the FRETsubstrate released quenching of fluorescence (excitation 488 nm andemission 590 nm).

The in vitro BACE FRET enzyme data for each of the Examples is providedin Table 2.

In Vitro BACE1 Cell-Based Assay

The cell-based assay measures inhibition or reduction of Aβ40 inconditioned medium of test compound treated cells expressing amyloidprecursor protein. Cells stably expressing Amyloid Precursor Protein(APP) were plated at a density of 45K cells/well in 384 well plates(Corning/BioCoat 354663). The test compounds were then added to cells in22-point dose response concentrations with the starting concentrationbeing 62.5 μM. The compounds were diluted from stock solutions in DMSOand the final DMSO concentration of the test compounds on cells was0.625%. The cells were cultivated overnight at 37° C. and 5% CO₂ in DMEMsupplemented with 10% FBS. After 24 h of incubation with the testcompounds, the conditioned media was collected and the Aβ40 levels weredetermined using HTRF (Homogeneous Time Resolved Fluorescence). The IC₅₀of the compound was calculated from the percent of control or percentinhibition of Aβ 40 as a function of the concentration of the testcompound.

The HTRF to detect Aβ40 was performed in 384 well plates (Costar 3658).The antibody pair that were used to detect Aβ 40 from cell supernatantswere ConfAb40 antibody (Amgen in-house) and biotinylated 6E10(BIOLEGEND). As an alternative to ConfAb40, a commercially availableantibody, Anti-beta Amyloid 1-40 antibody [BDI350] from Abcam,Cambridge, Mass. 02139-1517 (Product code: ab20068), may be used in thisassay. The concentrations were 0.35 μg/mL of ConfAb40 antibody and 1.33μg/mL of 6E10-biotinylated antibody, as well as 4.5 μg/mL ofStreptavidin Allophycocyanin Conjugate (ThermoFisher Scientific) in HTRFBuffer (1M Hepes pH 7.5, 1M NaCl, 1% BSA, 0.5% Tween 20).

The conditioned media was incubated with above antibodies andStreptavidin Allophycocyanin Conjugate for 30-60 minutes at 23° C. Thefinal readout was performed on Envision from PerkinElmer.

The in vitro BACE cell-based data for each of the Examples is providedin Table 2.

In Vitro Enzymatic Cathepsin D (CatD) FRET Assay

Recombinant CatD was expressed in CHO cells. The assay buffer for CatDwas 0.05 M citrate pH 3.5, 10% DMSO final, 5 mM CHAPS. The CatD enzyme(9 nM) was pre-incubated for one hour with inhibitors, typically inabout 1 uL of DMSO according to a serial dilution, is added thereto. Theassays was effectively started by the addition of different FRETsubstrates (20 nM for CatD) and the combination was incubated for onehour. The FRET assay was terminated with by addition of tris buffer,which raises the pH to neutrality, and the fluorescence was determined.The FRET substrate was a peptide with commercially available fluorophoreand quencher, on opposite sides of the CatD cleavage site. The CatDsubstrate peptide sequence was based on sequence #1 of Table 1 fromGulnik et al., FEBS Lett. 413(2):379-384 (1997). Proteolytic cleavage ofthe FRET substrate released quenching of fluorescence (CatD excitation500 nm and emission 580 nm).

Alternatively, a CatD assay may also be run according to the proceduredescribed in Yasuda et al., J. Biochem. 125(6):1137-1143 (1999). Inaddition, the CatD and Cathepsin E assays are described in InternationalPatent Application Publication No. WO2011069934.

The in vitro CatD FRET assay data for each of the Examples is providedin Table 2, conducted by the first procedure described above. As shownby the high micromolar CatD data (very poorly active or inactive againstCatD), the compounds disclosed herein possess the unexpected property oflittle to no ability to inhibit the activity of CatD. Thus, with thissurprising selectivity profile, the compounds provided herein arebelieved to minimize, reduce or completely eliminate any risk of retinalatrophy and abnormal development of the eye and of the retinal pigmentedepithelium as it relates to the normal function and activity of CatD.

In Vivo Inhibition of β-Secretase

Several animal models, including mouse, rat, dog, and monkey, may beused to screen for inhibition of β-secretase activity in vivo followingadministration of a test compound. This procedure may be used to showthat the compounds provided herein reduce the formation and/ordeposition of Aβ peptide in the cerebrospinal fluid (CSF) as well as inthe brain. Animals to be used in this experiment can be wild type,transgenic, or gene knockout animals. For example, the Tg2576 mousemodel, prepared and conducted as described in Hsiao et al., Science274:99-102 (1996), and other non-transgenic or gene knockout animals areuseful to analyze in vivo inhibition of Aβ peptide production in thepresence of test compounds.

Generally, 2 to 18 month old Tg2576 mice, gene knockout mice ornon-transgenic animals are administered test compounds formulated invehicles, such as cyclodextran, phosphate buffers, hydroxypropylmethylcellulose or other suitable vehicles. One to twenty-four hoursfollowing the administration of compound, animals are sacrificed, andbrains as well as cerebrospinal fluid (CSF) and plasma are removed foranalysis of Aβ levels and test compound concentrations (Dovey et al., J.Neurochem., 76(1):173-181 (2001)) Beginning at time 0, animals areadministered by oral gavage, or other means of delivery such asintravenous injection, an inhibitory test compound of up to 100 mg/kg ina standard, conventional formulation, such as 2% hydroxypropylmethylcellulose, 1% Tween80. A separate group of animals receive 2%hydroxypropyl methylcellulose, 1% Tween80 alone, containing no testcompound, and serve as a vehicle-control group. At the end of the testperiod, animals are sacrificed and brain tissues, plasma orcerebrospinal fluid are collected. Brains are either homogenized in 10volumes (w/v) of 0.2% diethylamine (DEA) in 50 mM NaCl (Best et al., J.Pharmacol. Exp. Ther. 313(2):902-908 (2005)), or in 10 volumes of 0.5%TritonX-100 in Tris-buffered saline (pH at about 7.6). Homogenates arecentrifuged at 355,000 g, 4° C. for 30 minutes. CSF or brainsupernatants are then analyzed for the presence of Aβ by specificsandwich ELISA assays based on ECL (Electrochemiluminescence)technology. For example, rat Aβ40 is measured using biotinylated-4G8(Signet) as a capture antibody and Fab40 (an in-house antibody specificto the C-terminal of Aβ40) as a detection antibody. For example, 4 hoursafter administration of 30 mg/kg oral dose of the test compound in 2%hydroxypropyl methylcellulose, 1% Tween80 (pH2.2) to 200 g male SpragueDawley rats, Aβ peptide levels are measured for reduction by X % and Y %in cerebrospinal fluid and brain, respectively, when compared to thelevels measured in the vehicle-treated or control mice. Alternatively,the antibody sold with the V-PLEX abeta40 Peptide (4G8) Kit,commercially available from Meso Scale Diagnostics (MSD), Rockville, Md.20850-3173 (Catalog NO. K150SJE-1) may be used in this assay.

This procedure may be used to show that the compounds provided hereinreduce the formation and/or deposition of Aβ peptide in thecerebrospinal fluid (CSF) as well as in the brain of a mouse or rat ateither 3 mpk, 10 mpk or 30 mpk (mpk=mg compound per kg weight of theanimal) dosing concentrations after 4 hrs.

Methods of Use

According to the amyloid cascade hypothesis, cerebral deposition ofamyloid-beta (Aβ) peptide is critical for Alzheimer's disease (AD)pathogenesis. Aβ peptide generation is initiated when β-secretase(BACE1) cleaves the amyloid precursor protein. De Meyer et al. re-affirmthe putative role that the accumulation of Aβ peptide in cerebral spinalfluid (CSF) in a subject plays in the progression of symptoms, initiallyrevealed as mild cognitive impairment, which ultimately leads to AD.Arch Neurol. 67(8):949-956 (2010). Aβ peptides generated from amyloidprecursor protein (APP) by proteolytic cleavage, such as by aspartylprotease enzymes, including β-secretase (BACE) and γ-secretase, likelyplay a causal role in AD pathogenesis (Tanzi et al., Cell 120(4):545-555(2005); Walsh et al., Neuron 44(1):181-193 (2004)). Although the precisemechanisms of Aβ toxicity are unclear, oligomeric forms of Aβ maycontribute to cognitive decline by altering synaptic structure andfunction (Palop et al., Nat. Neurosci. 13(7):812-818 (2010); Selkoe,Behav. Brain Res. 192(1): 106-113 (2008); Shankar et al., Nat. Med.14(8):837-842 (2008)). Transgenic mouse models that overexpress mutantAPP and produce high levels of Aβ show amyloid plaque deposition,synaptic deficits, learning and memory impairments, and other behavioralabnormalities (Games et al., Nature 373:523-527 (1995); Götz et al.,Mol. Psychiatry 9(7):664-683 (2004); Hsia et al., Proc. Natl. Academy ofScience USA (96): 3228-3233, 1999; Hsiao et al., Science (274): 99-102,1996, citing Harris et al, Neuron (68): 428-441, 2010).

For many years now, BACE1 has been a prime target for designing drugs toprevent or treat AD. Vassar et al., Lancet Neurol. 13:319-329 (2014).Several pharmaceutical companies are presently pursuing BACE1 inhibitorsin human clinical trials. Id. at abstract.

For example, MK-8931, a small molecule inhibitor of BACE1, was the firstmolecule to enter phase I clinical trials. Yan, Transl. Neurodegener.5(13):1-11 (2016) at page 4. MK-8931 was shown to have an excellentsafety profile with no immediately noticeable side effects. Id. Merckwas able to show that MK-8931 enters the brain and blocks β-secretase byshowing that MK-8931 significantly reduced CSF Aβ peptide concentrationsin a sustained and dose-dependent manner. Vassar et al., Lancet Neurol.13:319-329 (2014) at page 323. MK-8931 is currently evaluated in a phaseII/III clinical trial to assess the efficacy and safety of the compoundfor the treatment of AD patients with amnestic mild cognitive impairment(prodromal AD). Yan, Transl. Neurodegener. 5(13):1-11 (2016) at page 4.

Further, E2609, a BACE inhibitor identified by Eisai, showed significantreduction in Aβ peptide levels in the CSF and plasma in nonhumanprimates. Yan, Transl. Neurodegener. 5(13):1-11 (2016) at page 7. E2609did not show clinical significant safety concerns after repeated dosesup to 200 mg in a phase I clinical trial. Id. After 14d dosing the Aβpeptide level reduction in the CSF was statistically significantcompared to baseline (46.2% (25 mg), 61.9% (50 mg), 73.8% (100 mg),79.9% (200 mg)). Id. In November 2014, Eisai stated that a phase IIdose-finding study in patients with mild cognitive impairment (MCI) dueto AD or prodromal AD and a positive amyloid PET-scan will be conductedin collaboration with Biogen.

Additionally, companies are also developing therapies targetingasymptomatic patients. JNJ-54861911, which was first developed byShionogi & Co. in Japan and later in collaboration with Janssen,demonstrated an ability to cross the blood-brain barrier and todose-dependently reduce Aβ peptide concentrations. Yan, Transl.Neurodegener. 5(13): 1-11 (2016) at pages 5-7. For example, an oral doseof 95 mg once daily achieved Aβ peptide reduction of up to 95% in CSF.Id. In October 2015, Janssen and Shionogi launched a phase II/III trialtargeting asymptomatic subjects that are at risk for developingAlzheimer's dementia. Id.

Similarly, Amgen and Novartis announced in late 2015 a collaboration toco-develop Novartis' BACE inhibitor CNP520. Yan, Transl. Neurodegener.5(13):1-11 (2016) at page 8. The study is aimed at, inter alia, showingthat CNP520 “can slow down the onset and progression of clinicalsymptoms associated with Alzheimer's disease (AD) in participants at therisk to develop clinical symptoms based on their age and genotype.”https://clinicaltrials.gov/ct2/show/NCT02565511 (last visited Oct. 23,2016).

The compounds disclosed herein have been shown to modulate, andspecifically inhibit the activity of the β-secretase enzymes as shown inTable 2 for specific examples disclosed herein, thereby reducing thegeneration of Aβ peptide. Accordingly, the compounds provided herein areuseful for, for example, the prevention or treatment of β-secretaserelated diseases, including, but not limited to, AD. The compoundsprovided herein have the ability to modulate the activity of theβ-secretase enzyme, thereby regulating the production of Aβ peptide andreducing the formation and deposition of Aβ peptide in both the cerebralspinal fluid as well as in the brain, resulting in a decrease of Aβplaque in the brain.

More specifically, provided are the following uses for the compoundsdisclosed herein:

Provided are the compounds disclosed herein for use in reducing betaamyloid peptide levels in the cerebral spinal fluid of a subject.

Provided are the compounds disclosed herein for use in treating AD,cognitive impairment, or a combination thereof in a subject. In oneembodiment, the compounds provided herein are useful for treatingvarious stages and degrees of AD, including without limitation, mild,moderate and severe AD. In another embodiment, the compounds providedherein are useful for treating preclinical AD, mild cognitive impairment(MCI) due to AD, and dementia due to AD. In yet another embodiment, thecompounds provided herein may be used to treat prodromal subjects.

Provided are the compounds disclosed herein for use in treating aneurological disorder selected from mild cognitive impairment, Down'ssyndrome, hereditary cerebral hemorrhage with Dutch-type amyloidosis,cerebral amyloid angiopathy, degenerative dementia, dementia associatedwith Parkinson's disease, dementia associated with supranuclear palsy,dementia associated with cortical basal degeneration, diffuse Lewy bodytype of AD, or a combination thereof in a subject.

Provided are the compounds disclosed herein for use in reducingformation of plaque in the brain of a subject.

As previously discussed, in certain embodiments, the compounds describedherein are to be understood to include all stereoisomers, tautomers,isotopically-labelled forms thereof or pharmaceutically acceptable saltsof any of the foregoing or solvates of any of the foregoing or amorphousand crystalline forms (polymorphs) of any of the foregoing. Accordingly,the scope of the methods and uses provided in the instant disclosure isto be understood to encompass also methods and uses employing all suchforms.

Besides being useful for human treatment, the compounds provided hereinmay be useful for veterinary treatment of companion animals, exoticanimals and farm animals, including mammals, rodents, and the like. Forexample, animals including horses, dogs, and cats may be treated withcompounds provided herein.

Dosage, Formulation, and Route of Administration

The amount of compound(s) which is/are administered and the dosageregimen for treating neurological disorders and β-secretase mediateddiseases with the compounds and/or compositions disclosed herein dependson a variety of factors, including the age, weight, sex and medicalcondition of the subject, the type of disease, the severity of thedisease, the route and frequency of administration, and the particularcompound employed. A daily dose of about 0.01 to 500 mg/kg, or in someembodiments, between about 0.01 and about 50 mg/kg, and in still otherembodiments between about 0.01 and about 30 mg/kg body weight may beappropriate. In yet other embodiments, a daily dose of between about 0.1and about 10 mg/kg body weight may be appropriate and should be usefulfor all uses disclosed herein. The daily dose can be administered anumber of times a day such as from one to four doses per day.

While it may be possible to administer a compound disclosed herein alonein the uses described, the compound administered normally will bepresent as an active ingredient in a pharmaceutical composition. Thus,in another embodiment, provided herein is a pharmaceutical compositioncomprising a compound disclosed herein in combination with apharmaceutically acceptable excipient, such as diluents, carriers,adjuvants and the like, and, if desired, other active ingredients. Inone embodiment, a pharmaceutical composition may comprise atherapeutically effective amount of a compound disclosed herein.

The compound(s) disclosed herein may be administered by any suitableroute in the form of a pharmaceutical composition adapted to such aroute and in a dose effective for the treatment intended. The compoundsand compositions present herein may, for example, be administeredorally, mucosally, topically, rectally, pulmonarily, such as byinhalation spray, or parentally including intravascularly,intravenously, intraperitoneally, subcutaneously, intramuscularly,intrasternally, and by infusion techniques, in dosage unit formulationscontaining conventional pharmaceutically acceptable excipients such ascarriers, adjuvants, and vehicles.

For oral administration, the pharmaceutical composition may be in theform of, for example, a tablet, capsule, suspension or liquid. Thepharmaceutical composition is typically made in the form of a dosageunit containing a particular amount of the active ingredient. Examplesof such dosage units are tablets or capsules. For example, these maycontain an amount of active ingredient from about 1 to 2000 mg, fromabout 1 to 500 mg, and from about 5 to 150 mg.

For therapeutic purposes, the compounds provided herein are ordinarilycombined with one or more diluents or other “excipients” appropriate tothe indicated route of administration.

If orally administered on a per dose basis, the compounds providedherein may be admixed with lactose, sucrose, starch powder, celluloseesters of alkanoic acids, cellulose alkyl esters, talc, stearic acid,magnesium stearate, magnesium oxide, sodium and calcium salts ofphosphoric and sulfuric acids, gelatin, acacia gum, sodium alginate,polyvinylpyrrolidone, and/or polyvinyl alcohol, to form the finalformulation. For example, the active compound(s) and excipient(s) may betableted or encapsulated by known and accepted methods for convenientadministration. Examples of suitable formulations include, withoutlimitation, pills, tablets, soft and hard-shell gel capsules, troches,orally-dissolvable forms and delayed or controlled-release formulationsthereof. Particularly, capsule or tablet formulations may contain one ormore controlled-release agents, such as hydroxypropylmethyl cellulose,as a dispersion with the active compound(s).

Formulations for parenteral administration may be in the form of aqueousor non-aqueous isotonic sterile injection solutions or suspensions.These solutions and suspensions may be prepared from sterile powders orgranules using one or more of the carriers or diluents mentioned for usein the formulations for oral administration or by using other suitabledispersing or wetting agents and suspending agents. The compounds may bedissolved in water, polyethylene glycol, propylene glycol, ethanol, cornoil, cottonseed oil, peanut oil, sesame oil, benzyl alcohol, sodiumchloride, tragacanth gum, and/or various buffers. Other excipients andmodes of administration are well and widely known in the pharmaceuticalart. The active ingredient may also be administered by injection as acomposition with suitable excipients including saline, dextrose, orwater, and optionally comprising one or more of a cosolvent such aspropylene glycol or emulsifier such as, for example, Tween 80. Suchformulations may also include compounds such as a cyclodextrin (forexample, Captisol).

The sterile injectable preparation may also be a sterile injectablesolution or suspension in a non-toxic parenterally acceptable diluent orsolvent, for example as a solution in 1,3-butanediol. Among theacceptable vehicles and solvents that may be employed are water,Ringer's solution, and isotonic sodium chloride solution. In addition,sterile, fixed oils are conventionally employed as a solvent orsuspending medium. For this purpose any bland fixed oil may be employed,including synthetic mono- or diglycerides. In addition, fatty acids suchas oleic acid find use in the preparation of injectables.

The active ingredient may also be administered by injection as acomposition with suitable carriers including saline, dextrose, or water.The daily parenteral dosage regimen will be from about 0.1 to about 30mg/kg of total body weight, and in some embodiments may be from about0.1 to about 10 mg/kg.

For pulmonary administration, the pharmaceutical composition may beadministered in the form of an aerosol or with an inhaler including drypowder aerosol.

The pharmaceutical compositions may be subjected to conventionalpharmaceutical operations such as sterilization and/or may containconventional excipients, such as preservatives, stabilizers, wettingagents, emulsifiers, buffers etc. Tablets and pills can additionally beprepared with enteric coatings. Such compositions may also compriseexcipients, such as wetting, sweetening, flavoring, and perfumingagents. Accordingly, in yet another embodiment of the presentdisclosure, there is provided a method of manufacturing a medicament,the method comprising combining an amount of a compound according toFormula I with a pharmaceutically acceptable diluent to manufacture themedicament.

In yet another embodiment, the provided herein is a method ofmanufacturing a medicament for the treatment of AD, the methodcomprising combining an amount of a compound provided herein with apharmaceutically acceptable excipient to manufacture the medicament.

Combinations

While the compounds disclosed herein can be dosed or administered as thesole active pharmaceutical agent, they can also be used in combinationwith one or more compounds provided herein or in conjunction with otheragents. When administered as a combination, the therapeutic agents canbe formulated as separate compositions that are administeredsimultaneously or sequentially at different times, or the therapeuticagents can be given as a single composition.

The phrase “co-therapy” (or “combination-therapy”), in defining use of acompound provided herein and another pharmaceutical agent, is intendedto embrace administration of each agent in a sequential manner in aregimen that will provide beneficial effects of the drug combination,and is intended as well to embrace co-administration of these agents ina substantially simultaneous manner, such as in a single capsule havinga fixed ratio of these active agents or in multiple, separate capsulesfor each agent.

Specifically, the administration of compounds provided herein may be inconjunction with additional therapies known to those skilled in the artin the prevention or treatment of β-secretase, γ-secretase and/or otherreagents known in influence the formation and/or deposition of Aβpeptide, otherwise responsible for the formation of plaque in the brain.

If formulated as a fixed dose, such combination products employ thecompounds disclosed herein within the accepted dosage ranges. Thecompounds provided herein may also be administered sequentially withother known medicinal agents. This disclosure is not limited in thesequence of administration; compounds provided herein may beadministered either prior to, simultaneous with or after administrationof the known anti-inflammatory agent.

The foregoing description is merely illustrative and is not intended tolimit the disclosure to the described compounds, compositions andmethods. Variations and changes, which are obvious to one skilled in theart, are intended to be within the scope and nature of the invention, asdefined in the appended claims. From the foregoing description, oneskilled in the art can easily ascertain the essential characteristics ofthis invention, and without departing from the spirit and scope thereof,can make various changes and modifications of the invention to adapt itto various usages and conditions.

All references, for example, a scientific publication or patentapplication publication, cited herein are incorporated herein byreference in their entirety and for all purposes to the same extent asif each reference was specifically and individually indicated to beincorporated by reference in its entirety for all purposes.

What is claimed is:
 1. A compound of Formula I:

or a pharmaceutically acceptable salt, stereoisomer, or tautomerthereof, wherein:

R¹ is H or C₁₋₆ alkyl, wherein the C₁₋₆ alkyl is optionally substitutedwith 1, 2, or 3 F substituents; R^(1′) is H or C₁₋₆ alkyl, wherein theC₁₋₆ alkyl is optionally substituted with 1, 2, or 3 F substituents; R²is H, halogen, or OC₁₋₆ alkyl, wherein the OC₁₋₆ alkyl is optionallysubstituted with 1, 2, or 3 F substituents; R^(2′) is H, halogen, orOC₁₋₆ alkyl, wherein the OC₁₋₆ alkyl is optionally substituted with 1,2, or 3 F substituents; R³ is C₁₋₄ alkyl, optionally substituted with 1,2, or 3 F substituents; R⁴ is halogen; R⁵ is H or F; (i) R⁶ is H or F;and R⁷ is pyridyl or pyrazinyl, wherein the pyridyl or pyrazinyl isoptionally substituted with 1 or 2 substituents independently selectedfrom the group consisting of halogen, CN, C₁₋₆ alkyl, OC₁₋₆ alkyl,OCH₂C≡CH, and OCH₂C≡CCH₃, and further wherein the C₁₋₆ alkyl and theOC₁₋₆ alkyl are optionally and independently substituted with 1, 2, 3,4, or 5 F substituents; or (ii) R⁶ is pyridyl or pyrazinyl, wherein thepyridyl or pyrazinyl is optionally substituted with 1 or 2 substituentsindependently selected from the group consisting of halogen, CN, C₁₋₆alkyl, OC₁₋₆ alkyl, OCH₂C≡CH, and OCH₂C≡CCH₃, and further wherein theC₁₋₆ alkyl and the OC₁₋₆ alkyl are optionally and independentlysubstituted with 1, 2, 3, 4, or 5 F substituents; and R⁷ is H or F; andW is CH or N.
 2. The compound according to claim 1, wherein thestereoisomer of the compound is of Formula II:

or a pharmaceutically acceptable salt or tautomer thereof.
 3. Thecompound according to claim 1, wherein the stereoisomer of the compoundis of Formula IIIA:

or a pharmaceutically acceptable salt or tautomer thereof.
 4. Thecompound according to claim 1, wherein the stereoisomer of the compoundis of Formula IIIA′:

or a pharmaceutically acceptable salt or tautomer thereof.
 5. Thecompound according to claim 4, or a pharmaceutically acceptable salt ortautomer thereof, wherein: R² is F; and R^(2′) is F.
 6. The compoundaccording to claim 1, wherein the stereoisomer of the compound is ofFormula IIIB:

or a pharmaceutically acceptable salt or tautomer thereof.
 7. Thecompound according to claim 1, wherein the stereoisomer of the compoundis of Formula IIIB′:

or a pharmaceutically acceptable salt or tautomer thereof.
 8. Thecompound according to claim 1, wherein the stereoisomer of the compoundis of Formula IIIC:

or a pharmaceutically acceptable salt or tautomer thereof.
 9. Thecompound according to claim 1, wherein the stereoisomer of the compoundis of Formula IIIC′:

or a pharmaceutically acceptable salt or tautomer thereof.
 10. Thecompound according to claim 1, or a pharmaceutically acceptable salt,stereoisomer, or tautomer thereof, wherein:


11. The compound according to claim 1, or a pharmaceutically acceptablesalt, stereoisomer, or tautomer thereof, wherein:


12. The compound according to claim 11, or a pharmaceutically acceptablesalt, stereoisomer, or tautomer thereof, wherein: R¹ is CH₃; and R^(1′)is CF₃.
 13. The compound according to claim 1, or a pharmaceuticallyacceptable salt, stereoisomer, or tautomer thereof, wherein R⁴ is F. 14.The compound according to claim 1, or a pharmaceutically acceptablesalt, stereoisomer, or tautomer thereof, wherein: (a) R⁵ is H or F; andR⁶ is H; or (b) R⁵ is H or F; and R⁷ is H; or (c) R⁵ is H; and R⁷ is F.15. The compound according to claim 1, or a pharmaceutically acceptablesalt, stereoisomer, or tautomer thereof, wherein: R⁵ is H; and R⁶ is F.16. The compound according to claim 1, or a pharmaceutically acceptablesalt, stereoisomer, or tautomer thereof, wherein: (i) R⁶ is pyridyl orpyrazinyl, wherein the pyridyl or pyrazinyl is optionally substitutedwith 1 or 2 substituents independently selected from the groupconsisting of Cl, Br, CN, OCH₂CF₂CHF₂, OCH₂C≡CH, and OCH₂C≡CCH₃; or (ii)R⁷ is pyridyl or pyrazinyl, wherein the pyridyl or pyrazinyl isoptionally substituted with 1 or 2 substituents independently selectedfrom the group consisting of Cl, Br, CN, OCH₂CF₂CHF₂, OCH₂C≡CH, andOCH₂C≡CCH₃.
 17. The compound according to claim 16, or apharmaceutically acceptable salt, stereoisomer, or tautomer thereof,wherein: (i) R⁶ is selected from the group consisting of:

or (ii) R⁷ is selected from the group consisting of:


18. The compound according to claim 17, or a pharmaceutically acceptablesalt, stereoisomer, or tautomer thereof, wherein: (i) R⁶ is selectedfrom the group consisting of:

or (ii) R⁷ is selected from the group consisting of:


19. The compound according to claim 1, or a pharmaceutically acceptablesalt, stereoisomer, or tautomer thereof, wherein: (i) R⁶ is pyridyl orpyrazinyl, wherein the pyridyl or pyrazinyl is optionally substitutedwith 1 or 2 substituents independently selected from the groupconsisting of Br, CN, OCH₂CF₂CHF₂, OCH₂C≡CH, and OCH₂C≡CCH₃; or (ii) R⁷is pyridyl or pyrazinyl, wherein the pyridyl or pyrazinyl is optionallysubstituted with 1 or 2 substituents independently selected from thegroup consisting of Br, CN, OCH₂CF₂CHF₂, OCH₂C≡CH, and OCH₂C≡CCH₃. 20.The compound according to claim 1, or a stereoisomer thereof, whereinthe compound, or stereoisomer thereof, is selected from the groupconsisting of:(1R,5S,6R)-5-(5-((Z)-2-(5-bromopyridin-2-yl)-2-fluorovinyl)-2-fluorophenyl)-5-(difluoromethyl)-2-oxa-4-azabicyclo[4.1.0]hept-3-en-3-amine;(1R,5S,6R)-5-(5-((Z)-2-(5-chloropyridin-2-yl)-2-fluorovinyl)-2-fluorophenyl)-5-(difluoromethyl)-2-oxa-4-azabicyclo[4.1.0]hept-3-en-3-amine;6-((Z)-2-(3-((1R,5S,6R)-3-amino-5-(difluoromethyl)-2-oxa-4-azabicyclo[4.1.0]hept-3-en-5-yl)-4-fluorophenyl)-1-fluorovinyl)nicotinonitrile;(2R,5R)-5-(5-((Z)-2-(5-chloropyridin-2-yl)-2-fluorovinyl)-2-fluorophenyl)-2,5-dimethyl-2-(trifluoromethyl)-5,6-dihydro-2H-1,4-oxazin-3-amine;6-((Z)-2-(3-((3R,6R)-5-amino-3,6-dimethyl-6-(trifluoromethyl)-3,6-dihydro-2H-1,4-oxazin-3-yl)-4-fluorophenyl)-1-fluorovinyl)nicotinonitrile;5-((Z)-2-(3-((3R,6R)-5-amino-3,6-dimethyl-6-(trifluoromethyl)-3,6-dihydro-2H-1,4-oxazin-3-yl)-4-fluorophenyl)-1-fluorovinyl)pyrazine-2-carbonitrile;(2R,5R)-5-(2-fluoro-5-((Z)-2-fluoro-2-(5-(2,2,3,3-tetrafluoropropoxy)pyrazin-2-yl)vinyl)phenyl)-2,5-dimethyl-2-(trifluoromethyl)-5,6-dihydro-2H-1,4-oxazin-3-amine;(2R,5R)-5-(2-fluoro-5-((Z)-2-fluoro-2-(5-(prop-2-yn-1-yloxy)pyrazin-2-yl)vinyl)phenyl)-2,5-dimethyl-2-(trifluoromethyl)-5,6-dihydro-2H-1,4-oxazin-3-amine;(2R,5R)-5-(5-((Z)-2-(5-chloropyrazin-2-yl)-2-fluorovinyl)-2-fluorophenyl)-2,5-dimethyl-2-(trifluoromethyl)-5,6-dihydro-2H-1,4-oxazin-3-amine;6-((Z)-2-(3-((4R,5R)-2-amino-4-methyl-5-(2,2,2-trifluoroethoxy)-5,6-dihydro-4H-1,3-oxazin-4-yl)-4-fluorophenyl)-1-fluorovinyl)nicotinonitrile;(4R,5R)-4-(5-((Z)-2-(5-chloropyrazin-2-yl)-2-fluorovinyl)-2-fluorophenyl)-4-methyl-5-(2,2,2-trifluoroethoxy)-5,6-dihydro-4H-1,3-oxazin-2-amine;(4R,5R)-4-(2-fluoro-5-((Z)-2-fluoro-2-(5-(prop-2-yn-1-yloxy)pyrazin-2-yl)vinyl)phenyl)-4-methyl-5-(2,2,2-trifluoroethoxy)-5,6-dihydro-4H-1,3-oxazin-2-amine;5-((Z)-2-(3-((4R,5R)-2-amino-4-methyl-5-(2,2,2-trifluoroethoxy)-5,6-dihydro-4H-1,3-oxazin-4-yl)-4-fluorophenyl)-1-fluorovinyl)pyrazine-2-carbonitrile;(4R,5R)-4-(5-((Z)-2-(5-(but-2-yn-1-yloxy)pyrazin-2-yl)-2-fluorovinyl)-2-fluorophenyl)-4-methyl-5-(2,2,2-trifluoroethoxy)-5,6-dihydro-4H-1,3-oxazin-2-amine;(R,Z)-6-(2-(3-(2-amino-5,5-difluoro-4-methyl-5,6-dihydro-4H-1,3-oxazin-4-yl)-4-fluorophenyl)-1-fluorovinyl)nicotinonitrile;(R,Z)-5,5-difluoro-4-(2-fluoro-5-(2-fluoro-2-(5-(prop-2-yn-1-yloxy)pyrazin-2-yl)vinyl)phenyl)-4-methyl-5,6-dihydro-4H-1,3-oxazin-2-amine;(R,Z)-6-(2-(6-(2-amino-5,5-difluoro-4-methyl-5,6-dihydro-4H-1,3-oxazin-4-yl)-5-fluoropyridin-2-yl)-1-fluorovinyl)nicotinonitrile;and6-((Z)-2-(6-((3R,6R)-5-amino-3,6-dimethyl-6-(trifluoromethyl)-3,6-dihydro-2H-1,4-oxazin-3-yl)-5-fluoropyridin-2-yl)-1-fluorovinyl)nicotinonitrile;or a pharmaceutically acceptable salt or tautomer thereof.
 21. Thecompound according to claim 1, or a stereoisomer thereof, wherein thecompound, or stereoisomer thereof, is selected from the group consistingof:(1R,5S,6R)-5-(5-((Z)-2-(5-bromopyridin-2-yl)-2-fluorovinyl)-2-fluorophenyl)-5-(difluoromethyl)-2-oxa-4-azabicyclo[4.1.0]hept-3-en-3-amine;6-((Z)-2-(3-((1R,5S,6R)-3-amino-5-(difluoromethyl)-2-oxa-4-azabicyclo[4.1.0]hept-3-en-5-yl)-4-fluorophenyl)-1-fluorovinyl)nicotinonitrile;6-((Z)-2-(3-((3R,6R)-5-amino-3,6-dimethyl-6-(trifluoromethyl)-3,6-dihydro-2H-1,4-oxazin-3-yl)-4-fluorophenyl)-1-fluorovinyl)nicotinonitrile;5-((Z)-2-(3-((3R,6R)-5-amino-3,6-dimethyl-6-(trifluoromethyl)-3,6-dihydro-2H-1,4-oxazin-3-yl)-4-fluorophenyl)-1-fluorovinyl)pyrazine-2-carbonitrile;(2R,5R)-5-(2-fluoro-5-((Z)-2-fluoro-2-(5-(2,2,3,3-tetrafluoropropoxy)pyrazin-2-yl)vinyl)phenyl)-2,5-dimethyl-2-(trifluoromethyl)-5,6-dihydro-2H-1,4-oxazin-3-amine;(2R,5R)-5-(2-fluoro-5-((Z)-2-fluoro-2-(5-(prop-2-yn-1-yloxy)pyrazin-2-yl)vinyl)phenyl)-2,5-dimethyl-2-(trifluoromethyl)-5,6-dihydro-2H-1,4-oxazin-3-amine;6-((Z)-2-(3-((4R,5R)-2-amino-4-methyl-5-(2,2,2-trifluoroethoxy)-5,6-dihydro-4H-1,3-oxazin-4-yl)-4-fluorophenyl)-1-fluorovinyl)nicotinonitrile;(4R,5R)-4-(5-((Z)-2-(5-chloropyrazin-2-yl)-2-fluorovinyl)-2-fluorophenyl)-4-methyl-5-(2,2,2-trifluoroethoxy)-5,6-dihydro-4H-1,3-oxazin-2-amine;(4R,5R)-4-(2-fluoro-5-((Z)-2-fluoro-2-(5-(prop-2-yn-1-yloxy)pyrazin-2-yl)vinyl)phenyl)-4-methyl-5-(2,2,2-trifluoroethoxy)-5,6-dihydro-4H-1,3-oxazin-2-amine;5-((Z)-2-(3-((4R,5R)-2-amino-4-methyl-5-(2,2,2-trifluoroethoxy)-5,6-dihydro-4H-1,3-oxazin-4-yl)-4-fluorophenyl)-1-fluorovinyl)pyrazine-2-carbonitrile;(4R,5R)-4-(5-((Z)-2-(5-(but-2-yn-1-yloxy)pyrazin-2-yl)-2-fluorovinyl)-2-fluorophenyl)-4-methyl-5-(2,2,2-trifluoroethoxy)-5,6-dihydro-4H-1,3-oxazin-2-amine;(R,Z)-6-(2-(3-(2-amino-5,5-difluoro-4-methyl-5,6-dihydro-4H-1,3-oxazin-4-yl)-4-fluorophenyl)-1-fluorovinyl)nicotinonitrile;(R,Z)-5,5-difluoro-4-(2-fluoro-5-(2-fluoro-2-(5-(prop-2-yn-1-yloxy)pyrazin-2-yl)vinyl)phenyl)-4-methyl-5,6-dihydro-4H-1,3-oxazin-2-amine;(R,Z)-6-(2-(6-(2-amino-5,5-difluoro-4-methyl-5,6-dihydro-4H-1,3-oxazin-4-yl)-5-fluoropyridin-2-yl)-1-fluorovinyl)nicotinonitrile;and6-((Z)-2-(6-((3R,6R)-5-amino-3,6-dimethyl-6-(trifluoromethyl)-3,6-dihydro-2H-1,4-oxazin-3-yl)-5-fluoropyridin-2-yl)-1-fluorovinyl)nicotinonitrile;or a pharmaceutically acceptable salt or tautomer thereof.
 22. Apharmaceutical composition comprising a pharmaceutically acceptableexcipient and the compound according to claim 1, or a pharmaceuticallyacceptable salt, stereoisomer, or tautomer thereof.
 23. A method forreducing beta amyloid peptide levels in the cerebral spinal fluid of asubject in need thereof, the method comprising administering to thesubject a therapeutically effective amount of the compound according toclaim 1, or a pharmaceutically acceptable salt, stereoisomer, ortautomer thereof.
 24. A method for reducing the formation of plaque inthe brain of a subject in need thereof, the method comprisingadministering to the subject a therapeutically effective amount of thecompound according to claim 1, or a pharmaceutically acceptable salt,stereoisomer, or tautomer thereof.
 25. A method for treating aneurological disorder in a subject in need thereof, the methodcomprising administering to the subject a therapeutically effectiveamount of the compound according to claim 1, or a pharmaceuticallyacceptable salt, stereoisomer, or tautomer thereof; wherein theneurological disorder is selected from the group consisting of cerebralamyloid angiopathy, degenerative dementia, dementia associated withcortical basal degeneration, dementia associated with Parkinson'sdisease, dementia associated with supranuclear palsy, diffuse Lewy bodytype of Alzheimer's disease, Down's syndrome, hereditary cerebralhemorrhage with Dutch-type amyloidosis, and mild cognitive impairment,or a combination thereof.
 26. A method for treating a disease ordisorder in a subject in need thereof, the method comprisingadministering to the subject a therapeutically effective amount of thecompound according to claim 1, or a pharmaceutically acceptable salt,stereoisomer, or tautomer thereof; wherein the disease or disorder isselected from the group consisting of Alzheimer's disease and cognitiveimpairment, or a combination thereof.